Some 'Inactive' Drug Ingredients May Be Anything But, Study Finds

A bottle of generic aspirin
A bottle of generic aspirin
Photo: Tim Boyle (Getty Images)

Some inactive ingredients commonly found in medicines may not be so inactive after all, according to a new study published today. Researchers found evidence in the lab that several ingredients, including certain dyes and preservatives, are capable of affecting proteins, receptors, and other parts of our biology, possibly in important and noticeable ways. The findings aren’t proof that these ingredients can harm people, but they do suggest further research is needed.

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The scientists looked at thousands of inactive ingredients, also known as excipients. They screened them for their potential to interact or bond with any number of molecular targets found in the body’s cells, including those that regulate our levels of important neurotransmitters like dopamine. Once they found some that could plausibly affect the body, they then used two different methods in the lab to see whether and how each of these excipients affected the targets in human cells.

All in all, they identified 38 inactive ingredients that interacted with 44 different molecular targets. These included ingredients meant to be used as food dyes, preservatives, and disinfectants, such as D&C red no. 28, propylparaben, and benzethonium chloride. In some cases, the level of activity they saw from these interactions is what you would expect to see from the active ingredients of some drugs. The team’s findings were published in Science.

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“We show, at the molecular level, that some excipients modulate the activities of receptors important to human biology,” study author Brian Shoichet, a pharmaceutical chemist at the University of California, San Francisco, told Gizmodo in an email.

Though inactive ingredients have long been considered inert chemicals that pass through the body with no effect, some research is starting to challenge that assumption. Last year, for instance, a study found evidence that many ingredients are capable of triggering common food allergies or other hypersensitivities. This study seems to go further, highlighting several ingredients that may interact with the body the way that active ingredients are designed to.

One example was thimerosal, a derivative of mercury that’s used in some adult vaccines and other medical products as an antimicrobial preservative. They found evidence that it could bond to certain dopamine receptors in the brain and gut with high enough activity that it could make a “physiological effect by thimerosal plausible.” At the same time, they emphasized the lack of other evidence so far for any bodily effect of thimerosal, including the debunked link between vaccines and autism.

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The study last year, as well as this new one, were intended as proofs-of-concept only, a way of bringing attention to something that might be a problem but isn’t necessarily one. Shoichet and his team don’t want anyone to panic or to avoid taking any medication because of the findings.

“We do not prove they are toxic—far from it—but it’s nevertheless an area where the field can improve,” Shoichet said. “What this paper opens up is a new research direction. It starts a conversation.”

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In fact, it’s unlikely that most of the not-so-inactive ingredients Shoichet’s team found could even reach the types of molecular targets that they identified, since most targets were found outside of the digestive system, where drugs usually end up. Other experiments using animals showed that most of these chemicals didn’t reach the bloodstream in high enough concentrations to plausibly affect the body. That said, it’s possible that the situation could change under certain circumstances, such as a drug being taken via injection rather than as a pill (if the same inactive ingredients were used in both forms) or in people who take multiple medications or have a leaky gut that allows drug ingredients to seep into the bloodstream in higher concentrations.

The study was conducted partly with funding from the Food and Drug Administration and with collaboration from the pharmaceutical company Novartis. Shoichet offered praise to the FDA and Novartis for being willing to conduct this expensive study, knowing that the results could cause them a headache. The results may eventually lead to some changes in how their products and other companies’ drugs are produced.

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“Based on this early work, we are looking at next steps to determine if any excipients we currently use should be replaced,” co-author Laszlo Urban, the executive director and global head of preclinical safety profiling at the Novartis Institute for Biomedical Research, told Gizmodo via email. “We will continue to be led by science as we look at how to potentially make our medicines better. We believe this published research will also be helpful for others in the industry.”

Shoichet, for his part, hopes that people continue to build on his team’s work.

“It would be great to test inactive ingredients more comprehensively than we could afford to—we only scratched the surface,” he said.

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Science writer at Gizmodo and pug aficionado elsewhere

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DISCUSSION

How is this a new study?

I’ve known this for decades, and I’m not a freaking pharmacist or biochemist. The first hint I got was when my mother, a hyper sensitive Celiac, would get sick after taking her generic BP drugs. She had been ok, and it suddenly started making her sick.

Turned out the pharmacy was getting the drug from another manufacturer; and the inert binder was not GF.