Listening to Placebo, Especially in the U.S.

Why is the placebo effect intensifying among Americans—and why now?

Posted Oct 23, 2015

Three just-published studies on the placebo effect and medication caught my eye recently, not least for the questions they raise about treatment efficacy in medicine and the larger, fascinating implications of their analyses for understanding how the placebo response affects the brain itself.

In the first study, published in the September 30th issue of JAMA Psychiatry, researchers found that patients diagnosed with major depression revealed almost identical changes in brain scans when responding to a placebo as when given an actual antidepressant. The study found, too, that people showing a significant response to placebo were more likely to report higher levels of relief from medication, suggesting a connection tied to the magnitude of placebo response.

The study, led by Dr. Jon-Kar Zubieta of the University of Michigan, involved 35 patients diagnosed with severe and untreated depression. In the lead-in to the two-week randomized trial, all participants were given the same oral placebo, which was described to them as having fast-acting antidepressant effects. In the second phase, after a brief washout period, participants were switched to an actual antidepressant and given brain scans at regular intervals.

Mad in
Left: PET Brain scan of patient response to placebo. Right: PET Brain scan of patient response to antidepressant.
Source: Mad in

The results were striking. Participants showing a significant response to placebo, in ways activating their “mu-opioid system” (the part of the brain that minimizes pain and stress), were most likely to have a similar response when given an actual antidepressant. To this group of participants, differences between placebo and medication turned out to be negligible.

In an editorial focusing on the broader implications of the study, Dr. Maurizio Fava of the Massachusetts General Research Institute noted that its findings of a “biological response” to placebo were “consistent with the view that placebo treatment can, in fact, induce robust neurobiological changes,” in ways leading to significant “changes in brain functioning.” There were major ramifications for medicine, he added, when double-blind placebos were “roughly 80% as effective as antidepressants in randomized clinical trials.” “Classic conditioning” is a “possible mechanism for automatic self-healing,” he concluded, and positive expectations can be shown to increase placebo responses.

But if “a substantial portion of the neurological response to antidepressants can be accounted for by the placebo effect,” Justin Karter, news editor at Mad in, noted in commentary on the study, then such results must also have “serious implications for randomized control trial studies of antidepressant effectiveness.” Signs of those consequences “may already be apparent in a recent reanalysis of antidepressant efficacy versus placebo in major depression," he added, "which found that previous estimates of antidepressant efficacy compared to placebo had been significantly overestimated.”

That reanalysis, recently published in World Psychiatry, focuses on data held in the FDA archives about antidepressants approved between 1985 and 1997. Its authors, Arif Khan and Walter Brown, observe of their findings: “It quickly became apparent that many of the assumptions about the relative potency of antidepressants compared to placebo were not based on data from the contemporary trials but from an earlier era." Reviewing the data more carefully, they found that "the magnitude of symptom reduction was about 40% with antidepressants and about 30% with placebo." Accordingly, they write, it became evident "that the conventional wisdom of 70% response with antidepressants was at best an overestimate.”

Both studies indicate that placebo response rates “have increased over the last 30 years” (Peciña, et al), in ways supporting the findings of a third recent study, this time conducted on pain medication at McGill University, Canada. According to these researchers, an increase in the strength of placebo is both demonstrable and, curiously, unique to the U.S. Led by Dr. Jeffrey Mogil, a pain researcher at McGill, the team analyzed data from 84 drug trials for pain medication and found that its effectiveness relative to placebo had narrowed sharply between 1993 and 2013. Whereas trials from the 1990s gave the medication 27 percent higher efficacy than placebo, by 2013 that gap had shrunk to just 9 percent. Even more puzzling, regions with comparable data, such as Europe and Asia, showed no such change.

“I think it's really a matter of how big and how long the trials are, rather than some difference between the people in the countries,” Dr. Mogil told the Huffington Post. “But … [that’s] complete speculation.” One possible factor, noted Carolyn Gregoire in her report on the trial, is that “people have developed higher expectations of a drug’s effect because of the increasing fanfare around pharmaceutical trials.” If that’s true, it's likely also due to the prominent advertising campaigns used in the U.S. to market such medication.

All three studies point to an intensified role of placebo among Americans participating in clinical trials, including as a “robust” cause of neurobiological treatment.

That in turn raises significant questions about the way large-scale clinical trials are conducted here and whether Americans will continue to credit drug treatments for results that researchers increasingly are attributing to placebo alone. As Gregoire observed, “If the placebo effect continues on its current trajectory, American pharmaceutical companies may find it increasingly difficult to get consumers to buy new drugs.”  Follow me on Twitter @christophlane


Khan, A., & W. A. Brown (2015). "Antidepressants versus Placebo in Major Depression: An Overview." World Psychiatry 14.3, 294-300. (Full Text)

Fava, M. (2015). “Implications of a Biosignature Study of the Placebo Response in Major Depressive Disorder.” JAMA Psychiatry, 1-2. (Full Text)

Peciña, M., Bohnert, A. S., Sikora, M., Avery, E. T., Langenecker, S. A., Mickey, B. J., & Zubieta, J. K. (2015). “Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression.” JAMA Psychiatry, 1-8. (Full Text)

Tuttle, A. H., Tohyama, S., Ramsay, T., Kimmelman, J., Schweinhardt, P., Bennett, G. J., & Mogil, J. S. (2015). “Increasing Placebo Responses Over Time in U.S. Clinical Trials of Neuropathic Pain.” Pain doi: 10.1097/j.pain.0000000000000333