# The grapefruit juice effect

The medication I'm taking for insomnia interacts badly with grapefruit juice. This isn't much of a issue, yet; the cravings are still manageable. I only dream about grapefruit sometimes. I was never the kind of person to [blow my whole budget on the stuff](https://slatestarcodex.com/2014/06/09/minutes-from-the-michigan-rationalist-meetup/). The biggest problem, really, is that a mischievous imp or demon has been going around replacing all of the nonalcoholic drinks at every Bay Area house party with grapefruit Spindrift and *pamplemousse* LaCroix.

The most common reaction I get, when I bring this up, is "oh yeah, I \[had/have\] to avoid grapefruit because I \[was/am\] taking \[medication\]", with a different medication every time.

What's up with that?

Furanocoumarins, CYP3A4, and you
--------------------------------

There are a handful of cytochrome P450 ("CYP") enzymes in your liver that metabolize a huge variety of pharmaceutical compounds. The big ones are CYP2D6, CYP3A4, CYP3A5, and maybe a couple others.

Any time you're thinking of taking a medication, I recommend looking up how it's metabolized, especially if it's not the only thing you're taking. Two drugs that are metabolized by the same enzyme will very frequently have interaction effects.

You can also get pharmacogenetic testing done, to see whether you're likely to be producing an unusually high or low amount of one of these enzymes; this can be translated into dosage adjustments for many (most?) medications. The effect can be in either direction; CYP enzymes convert active forms of some drugs into inactive compounds, but for other drugs they actually convert an inactive precursor into the active form.

The relevant component of grapefruit juice -- or "GFJ", if you want to sound like a hip pharmacodynamicist -- is the furanocoumarins, a class of mildly-toxic chemicals related to coumarin. (Coumarin is present in some kinds of cinnamon; it's also why tonka beans are illegal in the US.) Furanocoumarins can [irreversibly](https://www.bmj.com/content/346/bmj.f1) inhibit CYP enzymes, especially CYP3A4 and CYP3A5; at that point you have to wait for your body to produce more enzymes, which takes days.

(Furanocoumarins also inhibit membrane transport proteins; independently of any CYP effects, this can make drugs less effective.)

## How real is this?

The effect sizes in the literature are not small. A review by [Hanley et al (2011)](https://pmc.ncbi.nlm.nih.gov/articles/PMC3071161/) demonstrates that for patients drinking moderate amounts of grapefruit juice, the blood concentration (AUC, i.e. integrated over time) is more than doubled for many drugs; in some cases it may increase by a factor of ten (although studies vary a lot).

On the other hand, many of these numbers got asterisks for "administration of GFJ in a manner deemed to be inconsistent with usual dietary consumption"; poking through a few papers, this typically means that they made their research subjects drink glasses of double-strength grapefruit juice three times a day (or "DS GFJ tid", as the kids say) for a few days. There are also some "acute GFJ exposure" annotations. (On the other other hand, even a single glass of single-strength GFJ is often enough to cause an AUC ratio of 2 or more.)

The paper points out a major hole in the usual "GFJ inhibits CYP3A" story: "Grapefruit juice is unique among CYP3A inhibitors because, when consumed in usual dietary volumes, only enteric CYP3A is affected. Therefore, GFJ has no impact on the pharmacokinetics of CYP3A substrate drugs administered intravenously, and does not prolong the plasma half-life of orally administered agents." 

In other words, grapefruit juice, which in ideal circumstances remains outside your liver, only gets to destroy the CYP enzymes in your gut; this is relevant for some drugs (those that are metabolized very quickly by CYP3A while still in the gut), but not most. They say that "grapefruit juice will only cause a clinically relevant interaction if all of the following conditions are met: (1) the drug is given orally; (2) the drug is significantly metabolized by CYP3A; and (3), the drug normally undergoes extensive first-pass metabolism by enteric CYP3A."

This seems pretty important! But I'm not sure how to square it with the papers they survey; if most drugs get through the gut without interacting much with CYP3A, I don't see why *any* quantity of GFJ should be expected to have these kinds of effects. They say that "[t]he number of drugs where GFJ causes a strong degree of CYP3A inhibition (AUC ratio ≥ 5) is quite small", but 5 seems like quite a high bar to me.

They end up concluding that "\[f\]or the majority of patients, complete avoidance of grapefruit juice is unwarranted", but I'm not sure I believe them.

I'm pretty confused about this!

Not all grapefruit
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[Liu et al (2017)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6152415/) found that, while red grapefruit has a little over 200 ug/g (dry weight) of bergamottin (a furanocoumarin), white grapefruit has only 11 ug/g. Pomelos, an ancestor of grapefruits, can have more than 600 ug/g, although some varieties have almost none.

Not just grapefruit
-------------------

This post was prompted by a friend of mine casually mentioning that they'd heard that other citrus fruits had the same interactions. This seemed plausible, and also kind of concerning; I've only ever seen warnings about grapefruit from doctors, medical documents, etc.

Fun fact: grapefruit, like lemons, limes, oranges, and most other popular citrus fruits, is a hybrid. There are four main ancestral citrus species, so you can make fun triangular and tetrahedral visualizations of citrus ancestry:

![A ternary diagram of citrus fruit ancestry](https://adam.scherl.is/assets/grapefruit/citrus.png)

This chart is missing one major ancestor, the micrantha, which is a component of most limes but not other citrus.

Looking at this chart, one might suspect that furanocoumarin content might be related to pomelo ancestry, and that many other kinds of citrus might also have furanocoumarins in somewhat lower amounts.

(I did some of this research while consuming a lime popsicle; I was not very happy to learn that Persian limes, unlike Key limes, have pomelo ancestry.)

But is that actually true?

According to one paper, "[The Distribution of Coumarins and Furanocoumarins in Citrus Species Closely Matches Citrus Phylogeny and Reflects the Organization of Biosynthetic Pathways](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142757)" (2015) by Dugrand-Judek et al, it is. Pomelos, as Liu found, are worse than grapefruit. It turns out that micranthas have an enormous amount of the stuff, and even Key limes are about as bad as grapefruits; Persian (Tahiti) limes, the most common species, are several times *worse*. Sweet oranges and some kinds of mandarin have very little, but Nasnaran mandarins have several times more than grapefruits do. Lemons have several times less than grapefruit. (I'm reading all of this off of a bar graph; the text of the paper only has numbers for a few species. There's supposedly a supplementary file with all of the data, but I can't figure out how to get it.)

A word of warning: Furanocoumarin content can depend very strongly on the particular variety of a citrus fruit, not just the species ([Alperth et al (2024)](https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/am-pdf/10.1002/pca.3499)), so take all of this with however much salt you take your limes with.

Spilling some tea
-----------------

One of the main furanocoumarins that gets mentioned in this context is bergamottin, as in bergamot, the citrus fruit used to flavor Earl Grey. I drink kind of a lot of Earl Grey, so I was curious whether it contains a significant amount of bergamottin.

[Arigò et al (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8303230/) looked into this. They found that Earl Grey has only about 0.01 mg/L of furanocoumarins; for comparison, lemon juice has 1.08 mg/L and bergamot juice has a whopping 29.3 mg/L. They didn't look at grapefruit juice, to my annoyance, but presumably it's somewhere between lemon and bergamot.

(The methodology of the paper is interesting. They obtain various beverages from "a local market", but make their *limoncello* by hand; the lemon extract has to sit for a month before it's ready. One has to wonder whether this entire paper is the result of a grad student trying to pass off their hobby as research.)

Not just CYP3A?
----------------

Wikipedia casually mentions that "Cytochrome isoforms affected by grapefruit components include CYP1A2, CYP2C9, and CYP2D6, but CYP3A4 is the major CYP enzyme in the intestine."

Diving into the abstract of a paper kind of at random: "Apparent selectivity toward CYP3A4 does occur with the furanocoumarin dimers. In contrast, bergamottin showed rather stronger inhibitory effect on CYP1A2, CYP2C9, CYP2C19, and CYP2D6 than on CYP3A4." ([Tassaneeyakul et al, 2000](https://www.sciencedirect.com/science/article/abs/pii/S0003986100918356?via%3Dihub))

Hanley et al claim that "Although the FCs inhibit multiple CYP enzymes in vitro, clinically significant inhibition by GFJ has only been unequivocally shown for CYP3A. For example, GFJ does not interact with theophylline (CYP1A2 substrate) or warfarin (CYP2C9 substrate)".

A lot of lists of grapefruit-affected meds, including on Wikipedia, use CYP3A4 metabolism as a major criterion. Based on my (shallow) research, it looks like this might be missing kind of a lot? Maybe you should just assume furanocoumarins affect anything metabolized by CYP? (And let's not forget those membrane transport proteins.)

(On the other hand, there are studies on the interaction of grapefruit juice with a wide range of specific drugs, so in many cases you don't need to use CYP enzymes as a proxy.)

Conclusion
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Maybe we should ban all citrus fruit, just to be safe.