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Sometimes a Placebo Is not a Placebo

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Placebos are used in clinical trials to demonstrate that an experimental drug is superior to the control or “inactive” pill, but sometimes placebos can contain “excipients” such as chemicals, dyes, allergens, or other confounding agents, which might unintentionally bring about symptoms in trial participants. Maryanne Demasi, Ph.D., discusses the issues that arise when placebos are not inert and how these issues may be addressed by the medical journals publishing trial results.

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Philip Tempest
March 9th, 2020 at 4:45 pm
Commented on: Sometimes a Placebo Is not a Placebo

Regarding your interest in the placebo use in JUPITER trial, have you made a request to AstraZeneca?  This is more likely to be successful than regulators or investigators since these will be under some sort of confidentiality agreement.  In my experience pharma companies will respond positively to requests from Cochrane.   No doubt you are aware that the rosuvastatin and placebo formulation numbers are respectively F12673 and F12832.

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Keith Crossfit
February 27th, 2020 at 1:37 pm
Commented on: Sometimes a Placebo Is not a Placebo

Currently, most vaccine trials use an adjuvant as the placebo, but not all, since some vaccines don’t contain an adjuvant. So they use another vaccine as the comparator.


The FDA issued guidelines years ago about using non-inert or “active” placebos in clinical trials. The guidelines were initially developed for “regular” drug trials and were done at the request of the medical community. Physicians were unable to determine whether a new drug was better than an old drug when the new drug had only been compared to an inert placebo during the clinical trials. What they wanted was for drug makers to do head-to-head comparative efficacy and safety trials. Thus, the FDA changed the requirements for clinical trials and this ushered in the era of using “active” placebos.


Under these guidelines, vaccine manufacturers were allowed to use vaccine antigen+adjuvant versus adjuvant trials. This permits them to assess antibody production but, of course, it obscures any safety issues solely due to the adjuvant which are, by design, bio-reactive. This applies to active placebos in regular drug trials, as well.

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Emily Kaplan
February 26th, 2020 at 2:36 am
Commented on: Sometimes a Placebo Is not a Placebo

This is fascinating and deeply upsetting. You have to wonder how any scientists designing a study could claim ignorance on this massive effect. Thank you for sharing!

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Malcolm Kendrick
February 17th, 2020 at 8:12 am
Commented on: Sometimes a Placebo Is not a Placebo

Nice succinct article MaryAnne. My main issue with the 'non-inert' placebo is that it helps to drive the Nocebo arguement. The statin trials have found virtually identical adverse effects between the statin and the placebo, and stated that adverse effects found in observational studies are due to the nocebo effect (you think you are going to get an adverse effect, so you get one). However, adverse effects in the statin trials have ranged from 6%, up to 80%. 6% in WOSCOPS, 80% in METEOR. It is hard to believe that a placebo can cause 6% adverse effect in one trial and 80% in another?

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Maryanne Demasi
February 18th, 2020 at 6:46 am

Yep, I agree!

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David Cumming
February 17th, 2020 at 1:37 am
Commented on: Sometimes a Placebo Is not a Placebo

Hi, Dr. Demasi. I liked your article, and I have a few questions. It seems clear that knowing what's in the Placebo is essential, and the ingredients should be published. As I clicked through to some of the links in the article, the discussion of the topic deepened and I got confused. Particularly the link referenced in the Notes regarding how "active" placebos are selected to mimic the side effects of the drug under investigation. The article says that this is to prevent "unblinding" the study. I can't tell from your essay what you are objecting to specifically. Is it the fact that the Placebo is a secret, the fact that the Placebo deliberately mimics the side effects of the drug? In the abstract, the author argues that "active" placebos may be advantageous and should be used more often in certain situations. Both? Do you believe this is incorrect and that "active" placebos should not be used?

Please forgive the remedial nature of my questions; I don't have any medical training, just an interest in understanding. Thank you for contributing to CrossFit Health. I learn tons from it!

Thank you!

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Maryanne Demasi
February 17th, 2020 at 2:34 am

Thanks David. Correct, sometimes the ingredients of a placebo are not disclosed and that concerns researchers, journal editors etc. If its not disclosed to trial subjects, then you have an issue of whether they gave "informed consent" to the experiment. On the other hand, sometimes you need an 'active placebo' to mimic the known side effects of a drug so that people in the control group can't work out whether they are on the drug or placebo (see the note). This article is more about an issue of disclosure rather than whether a placebo is active or not.

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Zdb Crossfit
February 16th, 2020 at 4:49 am
Commented on: Sometimes a Placebo Is not a Placebo

Thank you. Please keep doing this work and publishing these types of articles. Thank you much.

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