What substance is supposed to have no effect but can make people feel better, has no chance for a big monetary payoff but is worth billions, and is used in virtually every rigorous clinical trial but has no single, universal formulation?

The answer is the placebo. Hallmarks of good biomedical research, placebos are used throughout the world in double-blind, randomized controlled trials. And recently, they’ve come under intense scrutiny.

Beatrice Golomb, an associate professor of family and preventive medicine at UC San Diego, has spent years thinking about the use of placebos in modern medicine. In a paper published in the Annals of Internal Medicine last October, she raises concerns that placebos are not regulated by the US Food and Drug Administration, yet can have a direct impact on whether a drug is considered effective or not.

In one classic case Golomb considers, researchers in the...

Unfortunately, this is one of the few examples where this type of issue can be spotted, since, as Golomb points out, most placebo formulations are not reported. She analyzed more than 175 placebo-controlled trials published between January 2008 and December 2009 in the New England Journal of Medicine, the Lancet, the Annals of Internal Medicine, and the Journal of the American Medical Association to see if they listed placebo ingredients. In over 90% of the trials that used placebos in pill form, no formulation was mentioned. This “breaches basic scientific standards of rigor” and “compromises the foundation on which medical decisions are based, and on which the fate of lives may rest,” Golomb writes.

For its part, the FDA still views placebos as having no effect on either the body or the outcome of the trial, and correspondingly doesn’t seem to place too much emphasis on knowing the formulation of placebos used in different drug trials.


“Usually they tell us what’s in the placebo, so it’s not a secret,” says Robert Temple, director of the Office of Medical Policy at FDA’s Center for Drug Evaluation and Research. “But I can’t swear [they tell us] 100% of the time.”

Temple dismisses worries that placebo formulations should be made known more widely. “If it is one of the usual things—a little bit of lactose—we would not be worried about it, because everything has a little bit of lactose in it, and it won’t have any activity.”

But suspicion about the mysterious nature of placebos goes beyond just their composition. In the past ten years an increasing number of new drugs have been pulled from clinical trials because they were found to be no more effective than placebos, leading some to wonder if the placebo effect is strengthening. One of Golomb’s coauthors, McMaster University epidemiologist Murray Enkin, believes that drug trials against placebos aren’t a fair fight. “With a new drug, the implicit claim is that it is better than anything else, either more effective, or cheaper, or more stable,” says Enkin. “We should be comparing new drugs to the other best available drugs, not to something we think has no effect. And, if you can’t do that, at least you can be honest and say what it is you are comparing it to.”

Moreover, Jeremy Howick, researcher at Oxford University’s Centre for Evidence-Based Medicine in England, hopes that the whole practice of placebo use will be rethought. In some tests of antidepressants, he says, study participants are informed of side effects, such as dry mouth, during the consent process. If patients receive a pill and anticipate, and get, dry mouth, they might conclude that they have received the antidepressant, and therefore experience modified mood and reduced depression. Finding ingredients that can be safely added to placebos to mimic side effects of the drug being tested should be a major goal and would improve research, Howick says.

While changing the regulations on placebos could take years, University of Toronto researcher Robin Nunn hopes it could happen in his lifetime. Nunn harbors even more ambitious hopes that the use of placebos in clinical research will ultimately go the way of humoral medicine, phrenology, and bloodletting. After all, humoral medicine fooled the best medical minds for nearly two millennia before they realized that boiling down all of human biology to black bile, yellow bile, phlegm, and blood was just a trick of the mind—much like a placebo.

Interested in reading more?

Become a Member of

Receive full access to more than 35 years of archives, as well as TS Digest, digital editions of The Scientist, feature stories, and much more!
Already a member?