Roughly a century ago, a new fad diet began to sweep the United States. Hollywood starlets such as Ethel Barrymore supposedly swore by it; the citrus industry hopped on board. All a figure-conscious girl had to do was eat a lot of grapefruit for a week, or two, or three.
The Grapefruit Diet, like pretty much all other fad diets, is mostly bunk. If people were losing weight with the regimen, that’s because the citrus was being recommended as part of a portion-controlled, low-calorie, low-carbohydrate diet—not because it had exceptional flab-blasting powers. And yet, the diet has survived through the decades, spawning a revival in the 1970s and ’80s, a dangerous juice-exclusive spin-off called the grapefruit fast, and even a shout-out from Weird Al; its hype still plagues nutritionists today.
But for every grapefruit evangelist, there is a critic warning of its dangers—probably one with a background in pharmacology. The fruit, for all its tastiness and dietetic appeal, has another, more sinister trait: It raises the level of dozens of FDA-approved medications in the body, and for a select few drugs, the amplification can be potent enough to trigger a life-threatening overdose. For most people, chowing down on grapefruit is completely safe; it would take “a perfect storm” of factors—say, a vulnerable person taking an especially grapefruit-sensitive medication within a certain window of drinking a particular amount of grapefruit juice—for disaster to unfurl, says Emily Heil, an infectious-disease pharmacist at the University of Maryland. But that leaves grapefruit in a bit of a weird position. No one can agree on exactly how much the world should worry about this bittersweet treat whose chemical properties scientists still don’t fully understand.
Grapefruit’s medication-concentrating powers were discovered only because of a culinary accident. Some three decades ago, the clinical pharmacologist David Bailey (who died earlier this year) was running a trial testing the effects of alcohol consumption on a blood-pressure medication called felodipine. Hoping to mask the distinctive taste of booze for his volunteers, Bailey mixed it with grapefruit juice, and was shocked to discover that blood levels of felodipine were suddenly skyrocketing in everyone—even those in the control group, who were drinking virgin grapefruit juice.
After running experiments on himself, Bailey confirmed that the juice was to blame. Some chemical in grapefruit was messing with the body’s natural ability to break down felodipine in the hours after it was taken, causing the drug to accumulate in the blood. It’s the rough physiological equivalent of jamming a garbage disposal: Waste that normally gets flushed just builds, and builds, and builds. In this case, the garbage disposal is an enzyme called cytochrome P450 3A4—CYP3A4 for short—capable of breaking down a whole slate of potentially harmful chemicals found in foods and meds. And the jamming culprit is a compound found in the pulp and peel of grapefruit and related citrus, including pomelos and Seville oranges. It doesn’t take much: Even half a grapefruit can be enough to trigger a noticeable interaction, says George Dresser, a pharmacologist at Western University, in Ontario.
The possible consequences of these molecular clogs can sometimes get intense. “On the list of concerning food-drug interactions,” Dresser told me, “arguably, this is the most important one.” When paired with certain heart medications, grapefruit could potentially cause arrhythmias; with some antidepressants, it might induce nausea, vomiting, and an elevated heart rate. Grapefruit can also raise blood levels of the cholesterol drugs atorvastatin and simvastatin, prompting muscle pain and, eventually, muscle breakdown. One of the fruit’s most worrying interactions occurs with an immunosuppressive drug called tacrolimus, frequently prescribed to organ-transplant patients, that may, when amped up by grapefruit, spark headaches, tremors, hypoglycemia, and kidney problems. The citrus even has the ability to lift blood levels of drugs of abuse, including fentanyl, oxycodone, and ketamine.
The full list of potential interactions is long. “More than 50 percent of drugs on the market are metabolized by CYP3A4,” which inhabits both the liver and the gut, says Mary Paine, a pharmacologist at Washington State University. That said, grapefruit can really affect only intestinal CYP3A4, and will cause only a small fraction of those medications to reach notably higher concentrations in the blood (and sometimes only when fairly large quantities of juice are consumed—a quart or more). And only a small fraction of those medications will, when amassed, threaten true toxicity. Our bodies are always making more CYP3A4; stop eating grapefruit and, within a day or two, levels of the protein should more or less reset.
Professionals disagree on how to characterize grapefruit’s risks. To Shirley Tsunoda, a pharmacist at UC San Diego, “it’s definitely a big deal,” especially for the organ-transplant patients to whom she prescribes tacrolimus. Her advice to them is to indulge in grapefruit exactly never—and ideally, tacrolimus-takers should skip related citrus too. Tsunoda even advises people to check the labels of mixed-fruit juices, just in case the makers sneaked some grapefruit in, and she thinks twice when considering noshing on it herself. Paul Watkins, a pharmacologist at the University of North Carolina at Chapel Hill, is much less worried; his bigger concern, he told me, is that the fruit’s reputation as a nemesis of oral medications has been way overblown. He used to study grapefruit-drug interaction but abandoned it years ago, after “I came to the conclusion that it wasn’t very important,” he told me. Some concern is absolutely warranted for certain people on certain meds, he noted. But “I think the actual incidence of patients who have gotten into any kind of trouble or had serious adverse reactions due to taking their drugs with grapefruit juice is very, very small.”
Even the FDA seems a bit unsure of how it feels about the fruit. The agency has stamped the documentation of several grapefruit-sensitive medications with official warnings. But fact sheets for other drugs merely mention that they can interact with grapefruit, say to consult a health-care professional, or just counsel people to avoid drinking the juice in “large amounts.” And as Dan Nosowitz has reported for Atlas Obscura, several interacting drugs that bear warnings in Canada—among them, Viagra, oxycodone, the HIV antiviral Edurant, and the blood pressure medication verapamil—don’t mention any issues with grapefruit in the United States. (When I asked the agency about these discrepancies, a spokesperson wrote, “The FDA is continuously reviewing new information about approved drugs, including studies and reports of adverse events. If the FDA determines there is a safety concern, the agency will take appropriate action.”)
Very little solid data can precisely quantify grapefruit’s perils. Over the years, researchers have documented a number of isolated cases of citrus-drug interactions that prompted urgent medical care. But some of them involved truly exceptional amounts of juice. And citrus stans aren’t constantly dropping dead in clinical trials or nursing homes. Even when Bailey first presented his findings to the greater medical community, “people asked, ‘Where are all the bodies?’” Dresser, who was mentored by Bailey, told me. The paucity of data, Dresser contends, stems in part from health-care workers neglecting to check their patients for a history of juice-chugging.
For now, the conversation has mostly stalled, while grapefruit has served up even more mysteries. In the years since Bailey’s discovery, researchers have found that the fruit might lower the concentration of certain drugs, such as the allergy med fexofenadine, perhaps by keeping the lining of the intestines from absorbing certain compounds. New drugs are a particularly murky area, especially because grapefruit interactions aren’t a typical first priority when a new medication hits the market. The popular COVID antiviral pill Paxlovid, for instance, contains the CYP3A4-susceptible ingredient ritonavir. A Pfizer representative told me that the company is not concerned about toxicity. But Heil wonders whether grapefruit could mildly aggravate some of Paxlovid’s irksome side effects: diarrhea, for instance, or maybe the sour, metallic taste that reminds many people of … well, grapefruit.
That said, most grapefruit lovers need not despair. The fruit is still healthy—chock-full of vitamins and flavor—and yet is often overlooked, says Heidi Silver, a nutrition scientist at Vanderbilt University. Silver and researchers have shown that consuming grapefruit flesh or juice might be able to slightly lower levels of triglycerides and cholesterol. Technically, it can even play a role in weight loss: Snacking on a small portion before a meal can help people feel full faster. Then again, a glass of water will too. Just as grapefruit is not a miraculous vanquisher of fat, it isn’t a ubiquitous killer.
Even people on certain medications may be able to enjoy it if they consult an expert first. Heil’s own father absolutely adores grapefruit, and also happens to take an oral medication that can interact. Swallow them too close together, and he risks dizziness and fatigue. But he and Heil have found a compromise: He can have small portions of grapefruit or its juice in the morning, spaced about 12 hours out from when he takes his meds at bedtime. A few weeks ago, Heil (who thinks grapefruit is disgusting) even gave her dad the green light to enjoy a dinnertime cocktail that contained a small splash of the juice. Maybe the smidge of fruit affected his meds that day. But “it wasn’t going to be the end of the world,” Heil told me. To say that, after all, would have been an exaggeration.