Why does Paxlovid make things taste bitter?

Paxlovid can prevent severe illness from COVID-19 , but it comes with a price: In many users, the antiviral drug leaves a weird, metallic aftertaste that can last for days—a condition nicknamed “Paxlovid mouth.”

Now, researchers say they’ve figured out why. A component of Paxlovid activates one of the tongue’s bitter taste receptors even at low levels , which may draw out the yuck factor, the team reports this month in Biochemical and Biophysical Research Communications . The work could lead to ways to alleviate the unpleasant side effect.

The study is a “good first step” in teasing apart the mechanism behind Paxlovid mouth, says Alissa Nolden, a sensory scientist at the University of Massachusetts Amherst who was not involved with the research. But she says more work will be needed to truly understand why the metallic taste lingers for so long.

Paxlovid is composed of two proteins: nirmatrelvir and ritonavir. Nirmatrelvir blocks a key protein that SARS-CoV-2 needs to replicate. Ritonavir helps maintain the level of nirmatrelvir in the blood.

Scientists have suspected that ritonavir is the primary culprit behind Paxlovid mouth. It was originally used in HIV medications and was known to directly taste bitter. A recent study also demonstrated that the compound acts on several tongue receptors that respond to bitter taste .

However, ritonavir’s bitterness is short-lived, says Peihua Jiang, a molecular biologist at the Monell Chemical Senses Center, an independent research institute. So in the new study, he and colleagues looked more closely at nirmatrelvir. They added the protein to various groups of cells, each collection with a different member of the 25 human bitter taste receptors. They then identified the receptors that responded most vigorously to the compound by changes in a fluorescence marker in the cells.

Nirmatrelvir seemed to hone in on TAS2R1, one of the primary receptors responsible for the bitter aftertaste of antiviral medicines, the researchers found. The compound activated the receptor even when its concentration was relatively low, which could explain why Paxlovid causes a persistent bitter taste.

“As long as you have some certain level of Paxlovid nirmatrelvir in the body somewhere, that may be strong enough to stimulate the receptor,” Jiang says. Patients metabolize the drug differently, which Jiang believes could account for the fact that not everyone experiences Paxlovid mouth. One estimate suggests about 6% of people develop the side effect.

The results make sense, says Susan Travers, a taste researcher at Ohio State University who was not involved with the study. “I’m not surprised that [nirmatrelvir is] activating one or maybe a few bitter receptors because I don’t know how else you would get that sensation,” she says. “The surprise in the paper is that it is as specific as it is for TAS2R1.”

Jiang hopes the work could help researchers develop some sort of “bitter blocker” that would curb the bad aftertaste of Paxlovid. Some people refuse to take the COVID-19 drug because of the metallic side effect, he notes, so a blocker could potentially save lives.

But Nolden would like to see further confirmation in animal, or even human studies, that Jiang’s has found the right explanation. Still, she says she’s happy to see research into the Paxlovid mouth phenomenon. “It’s great to see progress being made.”