Study yields new insights into why some people get headaches from red wine

Red wine headache (RWH) might be caused by quercetin, which inhibits an enzyme that processes acetaldehyde in the blood.
Enlarge / Red wine headache (RWH) might be caused by quercetin, which inhibits an enzyme that processes acetaldehyde in the blood.
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As the holiday season kicks off this week, many will be making a consequential choice at dinner: red wine or white wine? And if your choice is red, will you be risking a headache? The fact that red wine can sometimes cause headaches in certain individuals (especially those prone to migraines) is common knowledge—so much so that the phenomenon ("RWH") even has its own Wikipedia page. The Roman encyclopedist Celsus wrote in his treatise De Medicina about the pain felt after drinking wine, while six centuries later, Paul of Aegina mentioned that drinking wine could trigger a headache.

But the science to date is largely unclear regarding which components of red wine are responsible, as well as the mechanisms behind the phenomenon. A team of California scientists has narrowed down the likely culprits to a flavonol called quercetin, according to a new paper published in the journal Scientific Reports, although they have yet to run experiments with participants prone to RWH to test their hypothesis.

It's a knotty issue because of the complexities of both wine and human genetics/physiology. Wine is basically water and alcohol, along with acids, dissolved sugars, and other compounds that lend color and flavor. For instance, the tannins in wine are polyphenolic compounds responsible for much of the bitterness and astringency in a given wine; they're derived from the skins and stems of the grapes, or as a result of aging in oak barrels.


Red wines typically have more amines, sulfites, flavonoids, and tannins, particularly a phenolic compound with antioxidant properties called resveratrol, also found in grape skins and leaves. That's because red wines are typically produced by soaking the grape skins in the mash (maceration), while producing white wines involves immediately draining the juice away from the grape skins. The grape skins also contain anthocyanins, which give the wine its red hue.

Drink enough alcohol of any variety and you'll probably get a hangover that involves a headache and at least some nausea. What's unusual about RWH is that even small to moderate amounts of red wine can induce a headache. It's common these days to blame sulfites, a preservative that is a natural byproduct of fermentation, but white wine and many other foods also contain sulfites. In fact, white wine often contains more sulfites than red wine. There is a small percentage of the population that is allergic to sulfites, but they typically get hives and have trouble breathing rather than developing a headache.

Then there are biogenic amines, another fermentation byproduct that contains things like histamine and tyramine, both of which have been linked to headaches. Genetics is a factor here; some people just can't metabolize histamine very effectively, for instance, because they don't produce enough of the enzyme responsible for breaking it down in the small intestine. And alcohol inhibits that enzyme to begin with, resulting in higher histamine blood levels. This can dilate blood vessels, causing a headache. Those amines are also present in aged cheeses, cured charcuterie, and dried fruits—all of which are typically consumed with red wine, exaggerating the effects even more. However, at least one study found no correlation between histamine and RWH, although the sample size was very small.

Tannins could play a role in RWH, since they can trigger the release of neurotransmitters associated with pain, along with phenolic flavonoids. This might explain why red wines are not equally associated with inducing headaches. A 2014 study involved 28 subjects drinking four half-bottles of Cabernet Sauvignon red wines: two from the Bordeaux region in France and two from South America. The Bordeaux wines caused headaches in 60 percent of the subjects, compared to 40 percent of the South American wines. The authors suggested that the Bordeaux wines contain higher concentrations of tannins and phenolic flavonoids for better flavors and aging potential, whereas the South American wines are meant to be consumed soon after their release.

The authors of this latest study decided to focus on the phenolic compounds in hopes of uncovering a likely mechanism for triggering headaches. It is already known that people with a certain dysfunctional genetic variant (ALDH2), the enzyme that metabolizes acetaldehyde (a well-known toxin), often become flushed or get headaches when consuming alcohol. So, the authors ran a series of enzymatic assays to determine how much different red wine flavonoids inhibited ALDH2.

They found that quercetin—specifically, a metabolite called quercetin-3-glucuronide—inhibits the ALDH2 enzyme and elevates the levels of acetaldehyde in the blood. Like resveratrol, quercetin is an antioxidant that is available in supplement form, but apparently it doesn't play well with alcohol. “When it gets in your bloodstream, your body converts it to a different form called quercetin glucuronide,” said coauthor Andrew Waterhouse, a wine chemist and professor emeritus at the University of California, Davis, Department of Viticulture and Enology. “In that form, it blocks the metabolism of alcohol.”


Different red wines will contain different levels of this flavonol since grapes produce it in response to sunlight. So Napa Valley Cabernets, for instance, will have more quercetin since the grapes are grown with clusters exposed to the sun. The degree of skin contact during fermentation, the fining process, and aging are other factors that influence levels of quercetin in red wine. The next step is to select wines with both low and high levels of quercetin and test them in a small human clinical trial.

“We postulate that when susceptible people consume wine with even modest amounts of quercetin, they develop headaches, particularly if they have a preexisting migraine or another primary headache condition,” said co-author Morris Levin, a neurologist and director of the Headache Center at the University of California, San Francisco. “We think we are finally on the right track toward explaining this millennia-old mystery.”

Scientific Reports, 2023. DOI: 10.1038/s41598-023-46203-y  (About DOIs).