Widely Covered Paper on Ranitidine-Cancer Link Retracted

Retraction Watch Staff

June 15, 2021

A paper linking the use of a wildly popular drug for heartburn to cancer has been retracted after the authors concluded that their widely touted finding appears to have resulted from a hiccup in the way they conducted their testing.

The 2016 article, in Carcinogenesis, has played a minor role in an ongoing class action lawsuit against the makers of ranitidine (sold as Zantac, among other brand names) claiming that use of the medication has caused cancer in more than 100,000 plaintiffs. And it was a key citation in a 2019 petition to the FDA urging that such drugs be recalled.

The FDA has been investigating contamination of ranitidine and a related drug with NDMA, a known human carcinogen at high doses. On April 1, 2020, the agency announced that, although its tests did not find concerning levels of NDMA in "many" of the samples it tested, it was recalling all products that contain ranitidine:

The agency has determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. As a result of this immediate market withdrawal request, ranitidine products will not be available for new or existing prescriptions or OTC use in the U.S.

The paper in Carcinogenesis, "Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine," was written by a pair of researchers at Syracuse University and Stanford University. It received a massive amount of coverage in the lay media, including ABC News, the Washington Post , the LA Times and other publications.

But as the retraction notice states, the FDA has found that the connection between ranitidine and NDMA that the authors reported might have resulted from issues with the instruments they used to test their samples:

This article is being retracted at the request of the authors. Recent research (1) has identified the potential for an analytical artefact associated with the use of gas chromatography that could have contributed to the levels of N-nitrosodimethylamine (NDMA) measured in urine samples containing ranitidine in this study. Given this artefact, the authors have informed the journal that their NDMA measurements are not reliable.

The authors, Teng Zeng and William Mitch, also have corrected a similar article in Environmental Science and Technology from 2015, titled "Contribution of N-Nitrosamines and Their Precursors to Domestic Sewage by Greywaters and Blackwaters." According to that notice:

Our study involved the measurement of N-nitrosamines, and their chloramine- and ozone-reactive precursors in different greywaters (e.g., laundry waters and sink waters) and blackwaters (e.g., urine and feces) contributing to sewage. On the basis of previous research suggesting that the pharmaceutical, ranitidine, serves as a chloramine-reactive precursor for N-nitrosodimethylamine (NDMA), our study included the collection of one urine and one fecal sample from each of two volunteers after the consumption of one 150 mg tablet of ranitidine. Our results indicated the occurrence of NDMA in the two urine samples collected after consumption of ranitidine, but not in the five samples collected without ranitidine consumption. We did not detect NDMA in the fecal samples. We had employed gas chromatography mass spectrometry (GC/MS) to measure NDMA. GC/MS has been a standard technique for the analysis of NDMA in water and wastewater samples by EPA Method 521(1) and by the U.S. Food and Drug Administration (FDA) for the analysis of NDMA in pharmaceuticals as recently as January 25, 2019.(2)
However, research has since identified the potential for an analytical artifact that could have contributed to the levels of NDMA measured in urine samples containing ranitidine in our study. Specifically, research has demonstrated that ranitidine is thermally unstable, and can convert to NDMA under high temperature conditions, such as might be encountered within GC injection ports.(3) For our GC/MS method, the injection port temperature started at 37 °C but was ramped to 230 °C over the first 20 s after injection. Unfortunately, given the potential for this analytical artifact, our NDMA measurements within urine samples collected after consumption of ranitidine are not reliable, since NDMA could have been formed during the sample analysis from any ranitidine present in the urine. Although the detection of NDMA in these specific urine samples was not reliable, this does not affect the conclusions of the study, since we did not conclude that ranitidine consumption was associated with an important contribution of NDMA or its chloramine- or ozone-reactive precursors to sewage.
The FDA has since developed two analytical methods to measure NDMA levels in pharmaceuticals that avoid this temperature-dependent analytical artifact by using liquid chromatography mass spectrometry (LC/MS).(4,5)

Mitch told us that, despite the journal notices:

As far as I know, the detections of NDMA in ranitidine tablets remain an issue (detections by LC/MS, which should not be affected by this artefact).

David Light, the CEO of Valisure, a company that tests drugs for NDMA — and which in September 2019 filed a petition with the FDA asking the agency to "request a recall and suspend sale of all lots of all products containing ranitidine" — said the retraction:

Is not surprising to us [given the known artefact issues], but I don't think it influences the issues about the concern over Zantac and ranitidine.

The Valisure petition cited the now-retracted study, and included this passage:

Arguably most important of all in vivo studies are those conducted in humans. One such study was completed and published in 2016 by Professor William Mitch and his team at Stanford University. 19 The study showed that healthy individuals, both male and female, that took Zantac 150 mg tablets produced roughly 400 times elevated amounts of NDMA in their urine (over 40,000 nanograms) in the proceeding 24 hours after ingestion. These results alone are extremely alarming, given NDMA has been implicated as an etiological agent for bladder cancer,20 however, the implications could be significantly worse given that NDMA is known to be heavily absorbed by the body instead of being excreted into urine.21

Light said Valisure started looking into a link between the heartburn drug and NDMA in 2019, but was unaware of the paper by Zeng and Mitch at the time. A spokesperson told Retraction Watch:

We have no immediate plans to retract mention of the study. Also, our Citizen Petition has been closed by FDA.