The other night, I came home from work exhausted. I walked the dog, fed her, put food in my mouth, grabbed a beverage from the fridge, took my usual dose of melatonin, and went to bed.

And then the Andrews Sisters’ rendition of “Chattanooga Choo-Choo” played over and over again in my head for the next eight hours.

Then it was time to get up.

Granted, I do sometimes have significant problems with insomnia. There is, after all, a reason I even have a “usual dose of melatonin.” But even on bad nights, I typically manage to drop off at least a little, even if it’s only for half an hour. No sleep at all is not the usual order of things.

It wasn’t until I was stumbling around that morning trying to create the appearance of being a sentient person-shaped clump of meat that my brain snagged on the beverage can on the nightstand.

Spindrift. Contains fruit juice.

Grapefruit.

The Mystery Begins

Memory is kind of a shitty mistress. I don’t want to say it’s cruel; I’m sure my memory is not some intentionally destructive mean girl sociopath or whatever. I imagine it more as a bog hag on quaaludes and Ambien whose peat hut is perpetually on fire, who is mostly preoccupied by trying to put out the fire with various inappropriate objects, like toast or underpants, and is only occasionally successful.

So, I do have all sort of memories regarding Facts of Life stored away somewhere in that hut. Some of them have probably been lost to the fires, but a lot of them are still there on a shelf or in a cupboard or rolled up in a sock. Facts like “grapefruit can significantly interact with the effects of many drugs.” But apparently the bog hag was preoccupied when I first bought the Variety Pack! of watered-down carbonated fruit juice that contained grapefruit, and also when I pulled one of these cans out to pour into my face, and only bothered to present this fact to me well after it was, you know…relevant.

But can I really blame that little can of highly diluted fruit juice for augmenting the waning effects of my stimulant ADHD medication and causing an entire night of non-sleep? I had no real evidence for it. Googling my medication and grapefruit juice together yielded statements like “ascorbic acid will decrease the absorption of the medication” –which confused me since the makers suggest mixing the medication in orange juice if there is trouble swallowing the capsules–or, more boldly, “does not interact.”

However, being stubborn and convinced of my own bullshit, I decided that if I could not blame the juice, I had to know why the hell not.

Drugs Inside You

So the thing about drugs is this: they go into your body at a certain entry point, after which they become absorbed into the rest of your body, where they reach some concentration at which they Do Stuff; and after a while of Doing the Stuff, your body eventually breaks down the drugs and turns them into pee, thus preparing your system to ingest new drugs.

Food in general can interfere with this process at every stage. The absorption part is what most drug labels are generally concerned with — take with food, take without food, that sort of thing.

Various kinds of fruit or fruit juices in particular can affect both absorption and breaking-down. Allegra (fexofenadine), for example, is pretty sensitive to having its absorption screwed up by multiple fruits, so don’t take it with your morning orange juice. And, to circle back, it is true that amphetamine-type ADHD medications don’t absorb as well in an acidic environment, so ingesting things that make your GI regions overly acidic might inhibit absorption somewhat if the timing is right. (The opposite is true, by the way, for certain antifungals–if you drink a soda with your ketoconazole, its absorption is way, way better.) But when I got to the question of urinary pH, I gave up, because it fucked with my head so much that I now have a personal vendetta against it and want to leave flaming bags of poop on its porch, in its mailbox, maybe down its chimney if I can get up there. But if Santa can do it, why can’t I?

Anyway. I digress.

Grapefruit in particular (together with its less-popular relatives pomelo and Seville orange, which are things I’ve only just learned exist) is famous for screwing with the breaking-down part of the process. In that it stops your body from doing it properly. But how, exactly? And which drugs does it mess with? I endeavored to find out.

It’s Enzymagical

So, different drugs are broken down (metabolized) by different kinds of enzymes in the body. A lot of drugs apparently get metabolized by various members of a superfamily of enzymes called cytochrome P450s, which, to me, sounds like a rad new brand of ridiculously expensive calculator. There are a lot of these enzymes, going about their day, slowly turning your drugs into pee. Just innocent pedestrians on the sidewalk of life.

Grapefruit is a violent maniac that hides out in alleys and waits for them.

Grapefruit especially hates this one buddo called CYP3A4, which breaks down god-knows-how many substances, including certain drugs–like blood pressure medications, some statins, immunosuppressants, several antidepressants, anti-psychotics and anti-anxiety medications, antihistamines, Viagra, and more.  Grapefruit will leap out of the shadows and just stab this guy in the throat with a railroad spike.

More accurately, a group of compounds in grapefruit called furanocoumarins may fully

inactivate whatever of these enzymes it finds. You’ll make new ones, but it takes a while. And while these enzymes are inactivated, your drugs are not getting broken down, and therefore not becoming pee, and potentially reaching higher concentrations than normal. In other words, your drugs are running around rampant like it’s The Purge. No laws, no consequences, setting fire hydrants on fire, marrying cats to dogs, licking all the surfaces on the subway interiors, putting candy corn on pizza, putting pomade in Boris Johnson’s hair, doing whatever it is that they do with no one to stop them.

My ADHD medication is not, however, metabolized by CYP3A4. Which is why most random sources discovered by Google told me that it “does not interact” with grapefruit.

But it is worth noting that, while grapefruit may hate CYP3A4 the most, this is not the only enzyme it does not like. Several other enzymes in this superfamily are, if not outright stabbed in the throat and left in an alley like CYP3A4, at least kicked in the groin and and left with their underpants pulled over their heads, or in medical terms, “inhibited.” These include CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

Amphetamine-type ADHD medications are partially metabolized by CYP2D6.

The Mystery Deepens

However.

The degree to which each of these other enzymes are inhibited is doesn’t seem to be fully understood, as yet. It is possible CYP2D6 may not be inhibited enough to make a clinical difference. Then again, it might be. The chemistry seems to indicate a significant inhibition with certain drugs, but studies with living bodies of some sort are needed to confirm that.

It also might be super unpredictable.

The grapefruit juice effect, as it is known, is also not predictable in relation to CYP3A4. Some drugs broken down by this enzyme don’t seem to be affected. Some drugs are more susceptible than others.

Also, it’s not just cytochrome enzymes it terrorizes. It will also smack around P–glycoproteins, which means it can further increase your exposure to your medication, but it can also assault organic anion-transporting polypeptides, which means it can decrease your absorption of medication. It also depends on the exact fruit cultivar, how the juice is processed, and the genetics of the individual consuming it. Sometimes the effect only happens with juice, pulp or segments, and not the whole fruit; and most studies on grapefruit juice don’t try to quantify the furanocoumarin content therein. And there’s probably a bunch of other confounding factors I didn’t read about because at this point I got super confused and gave up on this particular line of questioning, with the conclusion that some part of a grapefruit or grapefruit-like substance does something to some drugs and everything from that point is a bit of a shit show.

But Is it Just Grapefruit (and Pomelo and Seville Oranges) That Messes With Your Drugs?

No.

As far as I can tell, we don’t really know what all foods do to all drugs, or in what situations, or why. Grapefruit juice is probably the most famous for being the most potentially dangerous (and, I think, just because it’s a weirdo-sounding thing to even be dangerous), in that it can significantly increase the effect of some drugs that you really may not want any more of. Other interactions are often (but not always) less dramatic, or more about decreasing absorption/bioavailability.

In the realm of fruit, though–effects on cytochrome enzymes have been posited or wobbily-demonstrated with a variety of tropical fruits, mulberry, pomegranate, and so on. Under the general heading of “interactions,” well, the possibilities blow wide open. Apple and orange juice interact with atenolol and montelukast and, as mentioned, fexofenadine. Cranberry juice interacts with warfarin. Pawpaw and tangerine interact with digoxin. Orange juice enhances the absorption of aluminum and iron. Lime juice makes antimalarial treatments more effective. These are just some random things I plucked from this article, which has even more weird fruit-drug interaction facts, if you’re interested.

And this is just talking about fruit. There’s also potential interactions in…pretty much anything. I briefly looked into other interactions, including the possible effects of hibiscus (also included in Spindrift grapefruit beverages, for coloring) and oatmeal (because that was dinner) and at this point I’ve completely spun out. Because yes, hibiscus might interact with various things (caffeine, primarily), and even oatmeal is not completely innocent (decreases absorption of digoxin).

My overall impression, after combing through a great number of scientific papers that I only partially understood, is that any herb, food, drug, vitamin, mineral, bodily fluid, spice, or sufficiently be-particled draft of air can potentially interact with any other thing from that list. And, honestly, I’m just really impressed any of it works like it’s supposed to.

The Detective, Deciding She Doesn’t Even Like Grapefruit That Much Anyway, Gives Up and Goes Home to Watch “Grace and Frankie”

So, did the grapefruit juice extend the life of my ADHD medication? I can now respond with an emphatic “I do not have the tiniest fucking clue.” But, more importantly, I’m so thoroughly befuddled that I no longer care, and I can move on to the next shiny object.