From its name to its drug interactions, there’s a lot going on with grapefruit | Hacker News Reader

From its name to its drug interactions, there’s a lot going on with grapefruit

atlasobscura.com

393 pointsgilad166 comments

What the article does not mention is the connection of bitter taste to one of the two separate chemicals causing the drug interaction. It is a flavonoid called Naringenin.

https://en.wikipedia.org/wiki/Naringenin

On its own the chemical is tasteless but in grapefruit in connection with other chemicals common to a variety of fruits, the derived glycoside Naringin, becomes the principle compound providing the bitterness. The chemical is present in many fruits including fruits that typically considered bitter, but it makes grapefruit noticeably more bitter due to its higher concentration there. Perhaps humans are sensitive to the flavor due to the potentially toxic nature.

Strangely enough Naringenin is considered a toxin due to its interaction with human biochemistry but is not directly toxic. It allows increased sensitivity to other toxins. Though, to be fair, some drugs and nutrients are formulated in the GI tract due to microbial activity whose drug interaction and absorption can be directly modified by presence of this chemical.

https://en.wikipedia.org/wiki/Naringin#Toxicity

The link above indicates Naringin is a chemical isolate apart from 6',7'-Dihydroxybergamottin, the primary interacting furanocoumarin, and both independently suppress the P450 enzyme CYP3A4.

https://en.wikipedia.org/wiki/6%27,7%27-Dihydroxybergamottin

The article does mention other bitter fruits (descendants of pomelo) do share the “grapefruit effect”, but that you are less likely to consume large quantities of lemon juice, for example, compared with grapefruit juice.

The extra information you provide is really interesting.

I remember many years ago when I first moved to Asia, people looked at me wide-eyed whenever I took medicine with orange juice or a can of soda.

I dismissed it as some urban legend on the level of the fan-death [1] until a doctor explained to me the adverse interactions of citrus fruits on all sorts of medicine.

I have been taking my medicine diligently with water ever since, but it still amazes me how incredibly different the distribution of such common and potentially life-saving medical knowledge can be across countries and cultures.

[1] https://en.wikipedia.org/wiki/Fan_death

Being a little pedantic, the drug interactions part of the article applies to bitter citrus specifically: not just grapefruit (despite the title!), but not all citrus either. Typically “orange” is used to refer to sweet oranges, not sour oranges.

As to soda, I struggle to imagine a soda that has any amount of juice worth taking into account…

Sodas often contain significant amounts of ciric or phosphoric acid.

Per the article, the drug-interaction problem comes from furanocoumarins depleting your cytochrome P450. There's nothing in there to suggest that refined acid (as opposed to unprocessed juice) would include furanocoumarins.

Indeed, "citric" acid produced today comes from mold cultures that A) don't produce significant quantities of FCs, and B) even remove FCs from their environment by adsorption.

Sure of course, I was just replying to the question about fruit juice and sodas.

Orangina?

I once read that CocaCola is the largest consumer of lemon oil in the world. So I am sure their syrup has plenty of it.

I don't think this logic tracks - there are so many Cokes produced annually that even if every can had only 0.1 mL of lemon oil they'd still probably be the largest consumer.

Not too mention that the Coca-Cola company also own a staggering amount of more or less known brands, the bigger of which of course being Sprite and Fanta, which are likely large consumers of lemon oil.

Fresca is right on the line, with a can shown to increase serum concentrations of some drugs by 50%--- not enough to matter in most cases.

> As to soda, I struggle to imagine a soda that has any amount of juice worth taking into account…

It's not just the juice. The acidity level of your stomach affects absorption of many drugs - some are absorbed faster in an acidic environment and some are absorbed slower, which means drinking even Coca Cola (pH: 2.5) with your medication could potentially have the effect of negating your medication or increasing the effective dosage substantially, depending on the drug.

Your stomach is already much more acidic than Coca Cola

Indeed. It’s typically a pH of 1.

And your body is really good at buffering acids and bases. Once your stomach empties into your small intestine, bicarbonate is released which raises the pH to around 5.5 I believe which is necessary for digestive enzymes to work.

Think you'd be surprised. Coke pH is 2.5, and it seems that ideal human stomach pH is 1.5 to 2.5. Fun fact: you can use Coke to clean your toilets.

Across cultures and countries is not even the least of concerns, simply across doctors and other medical professionals, the communication to patients is not consistent. How this is solved is probably at the facility level and probably something that needs to be in the packet given to patients along with all those wonderful privacy and health notices.

This based on my mom doing chemo which came with other types of drugs to counter issues arising from that treatment and surgery. Suffice to say some doctors warn about the issue with grapefruit while others even dismissed the concerns. However this goes back to her quip about diabetes, you can get four opinions by asking three doctors.

My mother is doing chemo, and they definitely warned against grapefruit and the kind of oranges used in marmalade (not orange juice).

I'm wondering if this could be related to how common Pomelo (柚子) is in China (and maybe some other Asian countries, not sure), which per the article has the same effect and is also consumed in sizeable quantities.

Ooh, that's good intuition. Citrus genetics is complicated, but pomelo is the ancestor of grapefruit. (Bergamot and bitter orange are also closely related.)

I'm curious what you ever made, if anything, of the looks you would get for drinking ice water. I know it is considered very unhealthy with a strong taboo there (at least, my data is from China, not sure if applies to other asian countries). I once asked a Chinese friend would they rather their hypothetical child habitually drink ice water or smoke cigarettes, and she knows the health risks of cigarettes, and she was genuinely on the fence and torn.

What is the feared effect?

Water-borne diseases, I'm sure. It's easy for ice to be contaminated; if you go to a part of the world where tap water can't be relied on to be safe, skip the ice.

No, that’s not what he’s referencing. There’s a Chinese belief that cold water makes you sick. Even sanitized, filtered water and ice made from the same. The fear is over the temperature, and is akin to Korea’s fear of electric fans in its irrationality.

I understand, but my guess is that the origin of this belief was from times when cold water would make you sick because it was likely to be contaminated. Given that, it's not irrational at all. If you believe something that increases your survival but you believe it for the wrong reason, it still increases your survival.

That might be the origin of the belief, but it’s not what people are fearing today.

>Korea’s fear of electric fans

Say what? Do tell.

Oh my. You’re one of today’s lucky 10,000:

https://www.theatlantic.com/health/archive/2017/05/is-this-g...

I knew a girl from Hong Kong who carried the same belief so it's not just SK.

It's interesting the article didn't mentioned suicide, which I've seen mentioned before as a cause of the myth. The story goes that papers popularised the concept as a way to avoid specifically naming suicide as a cause of death, as a kind of shared understanding while preserving the honour of the families. But a lot of people took it seriously so the idea gained traction.

I consider most, if not all, tap water unsafe and recommend further filtration practices like reverse osmosis.

Secondly, I’ve seen many ice machines throughout my prior work and would strongly recommend avoiding ice cubes as most kitchens don’t clean these properly.

Cultural habits don't necessarily need a well defined cause and effect. The effect in such cases is that people think you are strange for not playing along.

The root of the habit in this case is Chinese medicinal beliefs. Here is a bit of a summary.

https://www.cheng-tsui.com/blog/hot-water-in-chinese-culture

"In traditional Chinese medicine (中医, zhōng yī), hot water is used to expel excess cold and humidity from the body, and it is believed to promote blood circulation. This helps detoxify the body and relax the muscles. Cold water supposedly has the opposite effect, slowing organ function and causing painful muscle contractions. Thus, hot water is often touted as the cure for everything from sore throats to stiffness to cramps to fatigue."

Of course, modern people also know that untreated water is not safe. That doesn't explain an aversion to cold bottled water or other drinks though, which while far from absolute is more common than it is in Western countries.

I remember somebody mentioned if they drink ice water after exercising and getting really hot, it can cause them to pass out.

Anybody have the details on that effect?

It's true and it happens when nerves around the stomach (called vagus nerve) react to the cold by sending a signal to the brain. Because among other effects signals from the vagus nerve reduce cardiac frequency, you can indeed pass out as a result.

Not a doctor, but it happened to my wife and it was a little scary.

In China there was a longstanding practice of using nightsoil (i.e. human feces) as fertilizer. The health risks are great and doing it safely requires strictest adherence to hygiene protocols. Everything is boiled for safety, even lettuce is wilted in the pan. It's no surprise that ice water gets you the crazy look.

Food taboos oftentimes make sense. Sometime ago someone mentioned traditional, cyanogen-rich varieties of cassava, which are pest-resistant but require boiling for hours in an open pot. If you omit that you end up with motor neuron disease, konzo as they call it, but only after several years. So it's not surprising that superstitions sprang up around the plant, some of which are actually protective.

Oh wow, my time to shine!

Grapefruit juice combined with Vitamin D drops caused me a lasting headache, which, in hindsight, was like a sinus infection without the sinus infection part, but including the typically incredibly stiff neck.

Lasting here means a whole month. One month of continuous headache. Not headaches. One gigantic headache. Mostly 7/10, two times 9/10, at which points we called the ambulance because I couldn't take it anymore.

Don't ever mix grapefruit juice with anything.

That’s fascinating. Do you mean that you mixed vitamin D with grapefruit juice once and got a headache that lasted a month? Or were you continuing to drink grapefruit juice and take D during that month?

How much vitamin D were you taking?

How much time was there between taking vitamin D and drinking grapefruit juice?

I had a grapefruit-juice phase (those only lasted days) and drank pretty much nothing else. I took the vitamin D for reasons I forgot.

There was no time in between taking it and drinking the juice. It was what I drank most of the day.

One can take a few of these drops (liquid, in case that's unclear) every day, but that makes my stomach gas up massively for some reason.

One can take them once a week, too, but then he had to take the whole weekly dosage at once. Apparently it doesn't matter. I don't remember how much it was, but I'm talking about one or two dozen water droplets here. I'm sorry, I don't know how to express this any better.

The headache started maybe two hours later.

If I'm understanding you correctly, there was a period of a few days where you were both drinking grapefruit juice and taking vitamin D, and your headache lasted for a month afterwards?

Yes, I took a weekly dosage of vitamin D once during these days. It was a friday afternoon in february or march. I remember this, because during that time I had a few dentist visits scheduled, which I cancelled.

It seems to me like you are describing some kind of viral meningitis

They phoned an ambulance twice, so if it was something fairly obvious like this it's a reasonable assumption that would have come to light at the hospital.

I've seen similar warnings about grapefruit before, but the article is the first time I've seen the specific mechanism discussed in this kind of depth. It's also the first time I've seen mention that all "bitter citrus" includes the problematic compounds, including lime and "sour orange" (is that the same as blood orange?).

At least for me, it would be better if the headlines would cover this as the broader "bitter citrus", instead of grapefruit specifically. I can't stand grapefruit, so I never paid much attention to the warnings, but I love lime and blood orange, which means further investigation is warranted. TFA says it's "unlikely" anyone would consume enough lime to have an effect, but how much is "enough"?

> "sour orange" (is that the same as blood orange?).

Not. Sour orange is Citrus x aurantium whereas blood oranges are a type of cultivars of the common orange Citrus x sinensis sharing a red mutation. Both are hybrids but have different ancestors.

Sour is inedible in fresh and must be processed, whereas the blood group are small but deliciously acid.

Sour orange pie is a thing though (tastes much like key lime pie).

Citrus aurantium are used as a source of synephrine, a stimulant similar to ephedrine, which also interacts with various medication. According to OPs article, grapefruit works in a different way.

This article also mentions grapefruit: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655712/

FWIW, I don't think "sour orange" referred to blood orange. I believe it refers to Bitter Orange/Seville Orange: https://en.m.wikipedia.org/wiki/Bitter_orange

I think blood oranges are sweet.

Blood oranges have very similar interactions to grapefruit, so it likely is referring to them.

The NHS provides a very in-depth article on this (their health information is generally top notch). I would recommend giving it a read: https://www.nhs.uk/news/medication/prescription-drugs-and-gr....

In the article they state:

> How much grapefruit is too much grapefruit?

> The researchers report that furanocoumarins are present in all forms of grapefruit (freshly squeezed juice, frozen concentrate and whole fruit).

> One whole grapefruit or 200ml of juice is sufficient to cause enough of an increase in the concentrations of active drugs to have an effect on the body, and therefore could cause side effects.

I presume this would hold for other "bitter citrus" as well.

———————————————

The listed potential health effects are quite significant:

> - Torsade de pointes (a form of abnormally rapid heartbeat that starts in the lower chambers of the heart, which can increase the risk of sudden death)

> - Complete heart block (where there is no transmission of the electrical pulses between the upper and lower chambers of the heart that are needed to make it beat)

> - Rhabdomyolysis (breakdown of muscle fibres that leads to the release of muscle fibre contents, including myoglobin which breaks down into substances that can damage the kidney)

> - Nephrotoxicity (kidney damage)

> - Myelotoxicity (damage to the bone marrow)

> - Venous thrombosis (blood clot)

> but how much is "enough"

Indeed! My wife literally eats lemons like they were oranges. Probably something for us to look out for!

> My wife literally eats lemons like they were oranges

Those are probably Meyer lemons, that is a hybrid (lemon x tangerine if I remember correctly) so is sweeter than the true lemon (or maybe your wife is simply strange ;-)).

Especially in the Bay Area (the user name hints at that), this is a good guess. Most of the trees you'll find a few to a block are Meyer lemons. One of the things I miss about the Bay, along with the pervasive jasmine, and persimmon season.

Just was curious and checked it. It seems that there is not much lemon in Meyer lemons:

(citron x (pomelo x mandarin))

I assume that, having a little pomelo blood could trigger the same chemical interactions shown in the article.

She is definiltely just strange. She loves anything sour, and will eat any lemon anywhere.

She's had to stop recently after being shouted at by her dentist, for stripping away a lot of her enamel with all the citric acit in the lemons.

I feel like people are more likely to consume a larger quantity of grapefruit than lime, though.

People eat grapefruit by itself, or juice. Lime juice is typically a garnish or a flavor used in less quantity. Not to mention size of the fruit.

Maybe, maybe not. A good cup of nimbu pani has at least two full limes squeezed into it, and there's no law saying you have to only drink one.

Let me put it slightly differently: I don't hate grapefruit, but I don't especially care for it, and I really like lime. I'm pretty confident I consume more lime than grapefruit on a gram-for-gram basis.

It's not often consume in comparable amounts is my point.

Even two limes is half a grapefruit.

My grandfather used to eat grapefruit every day, but had to give it up when he was prescribed Warfarin (a blood thinner). Ironically it seems that it would have been just fine for him to continue so long as he stuck to religiously eating grapefruit every day. He would have needed a substantially lower dose of the drug, but Warfarin is one where you adjust the dose a lot for each patient anyway: the manufacturer recommends starting with 6mg and ending up anywhere from 0.5 to 10mg depending on the patient's response [0].

He was also hospitalised several times, both for his heart problems and stomach cancer. I wonder if hospitals keep grapefruit on hand for patients like this, or if they ban it altogether.

[0] https://www.nps.org.au/australian-prescriber/articles/how-to...

> the manufacturer recommends starting with 6mg and ending up anywhere from 0.5 to 10mg depending on the patient's response

I tried to explain binary search to my gp when she was trying to find my dose of thyroxin. Unfortunately, according to her, a too high does carries a lot of unpleasant side effects - so linear search it was.

Yeah, binary search where you don't know what the upper bound is with a narrow therapeutic index drug is not necessarily the best option

We pretty much did binary search to find my lithium levels. The lethal concentration of lithium is very close to the therapeutic range, but we couldn’t afford to spend long on low doses (since you have to take blood tests to assess effective dosages.)

If you keep a good diary you can limit the blood tests to 1-2 times per year and assess therapeutic effect using self-reporting.

My dad used to take warfarin too and keep a very steady diet of dark leafy greens (his poison of choice he wouldn’t give up). There are meds now that are less dependent on food, your grandviejo may want to ask about.

That 1 glass of grapefruit 10x the potency of Tylenol is shocking, but even more so, how we don't seem to have a reasonable system of 'public awareness' for these things.

We 'make discoveries' and then just hope it wades through the network of doctors, pharmacists.

Much like with COVID 'communications' it's kind of a disaster. There's nowhere for me to simply find out 'the latest official information' for my province/country in a reasonable and coherent way - a lot of web sites flush with tons of secondary, bureaucratic information, whereas there should be a 'single web page' with the current 'highly relevant information' and another 'single page' to visit with precautions and up-to-date instructions if you're symptomatic. Details on the side.

Like the ostensible annual visit to the doctor, I wonder if each healthcare system should put out it's annual list of 'key information' in something easily digestible, written for those with Grade 10 reading ability because that's the lowest common denominator and frankly the intellectual level we're all at when not focusing.

So thanks (I guess?) HN! No more grapefruit juice when I'm sick or having a headache with the ... Tylenol. Hey zeus.

Hw is that not on the label ...

For the most up to date COVID information there's this from WHO:

https://www.who.int/emergencies/diseases/novel-coronavirus-2...

> These materials are regularly updated based on new scientific findings as the epidemic evolves. Last updated 5 October 2020.

I had no idea that grapefruits had so much risk associated with them if you're taking medication. Most of the ones listed in the article are actually hugely popular, I wonder how many people took some innocent stuff like Tylenol and then drank some grapefruit juice and felt weird, without realizing what happened.

https://en.wikipedia.org/wiki/Grapefruit%E2%80%93drug_intera...

They interact with so many drugs, if you take any medication for chronic illnesses, chances are you should not eat any grapefruit for the rest of your life. Also whether a drug is affected by it or not is not clear, so the common advice is just to avoid the fruit whatever the drug you're taking.

It's one of my favourite fruits, and not being able to eat it once in a while hurts. Though I'm not sure how _dangerous_ it really is. Does it affect the half-life of a drug by 5%, or by 100%?

TFA says it increases the bioavailability of felodipine, the drug where the effect was first noticed, by about a factor of 5. For most prescription drugs for chronic illness, you probably do not want to find out what happens when you move to 5x the effective dose.

Depends on the dose and drug. 5x the dose of adderall is probably pretty fun.

Adderall/Vyvanse/Amphetamines don't interact well at all with vitamin C, of which grapefruits are full of. So sadly enough, you don't get any 5x intake boost with the enjoyable meds. Would have been way too much fun ;)

Isn't the vit C thing just because of acidity? Combining with a teaspoon of NaHCO3 would cancel that out, no?

But apparently the effect lasts up to 12 hours, vitamin c should be gone from the stomach by then. Grapefruit has been anecdotally recommended for MDMA (an amphetamine).

The reason it's recommended for MDMA is because it inhibits the CYP3A4 enzyme which metabolizes MDMA (3,4-Methylenedioxymethamphetamine) to MDA (3,4-Methylenedioxyamphetamine). MDA is more neurotoxic than MDMA which is why it's advised to reduce the amount your body intakes.

The majority of adderall breaks down through the urea cycle due to urine acidity. Enzymes don’t play as significant a role as they do for other drugs. That’s why baking soda is the best potentiator for amphetamines, as it neutralizes urine acidity.

For anyone considering actually doing this, beware that it needn't take much baking soda to be harmful. People have died from overdosing.

Maybe someone with journal access can dig out dosage ranges from any of these many sources: https://scholar.google.com/scholar?q=related:4ssWhTcQeYEJ:sc...

If by “fun” you mean think-your-heart-is-about-to-literally-explode and lie down in fear for 8 hours.

(Source: have accidentally double dosed my amphetamine Rx. A 5x dose would probably be lethal.)

As someone prescribed Adderall, to my knowledge, grapefruit juice (and citrus in general) will inhibit the absorption so if anything, it would just lower the effectiveness of a typical dose.

Even for "some innocent stuff like Tylenol", as the original comment puts it, you do not want to be taking 5x the dose. This is a very harmful drug in (not very) large quantities.

I know of somebody whose boyfriend ended things with her, she took a load of tylenol to end her life, but the doctors managed to resuscitate her. When she came to, she said to her mother "I'm so glad I didn't kill myself over that bastard". A week later she died from liver failure.

Tylenol is most of the most deadly (in terms of effective dose vs harmful dose) of anything commonly used.

That's a standard thing with Tylenol/Paracetamol. You can recover from the initial overdose, but then the metabolites build up in your liver over the next few days and trash it beyond any hope of repair.

At that point it's either a transplant or death.

The scary thing is that it's incredibly easy to overdose by accident. For some people the lethal dose is less than twice the recommended dose, and if you're in a lot of pain - e.g. from a dental abscess - you can easily overdo it.

I'm on a blood pressure drug. My pharmacy ran out of the dose I needed and substituted a 2x size, with instructions to cut the pill in half. I ended up forgetting about the substitution and took the 2x dose daily for a couple of months. Didn't find out until I went to renew the prescription and was told I was trying to refill it too early. Suddenly the recent dizzy spells I had were easily explained.

I think I knew about interactions with benzos, but didn’t know about Tylenol, Aleve, caffeine (!?) or protease inhibitors.

innocent stuff like Tylenol

On a pedantic note, acetaminophen should not be considered innocent, but rather considered to be something very easy to get too much of because it’s in friggin’ everything. Cough syrup, Tylenol, many opioids that your doctor might prescribe. Read those labels, because if you take some Tylenol for those aches and pains and wash it down with some cough syrup for that cold, your liver might want to have a word with you.

Acetaminophen is added to opiates to make sure there are bad side effects if you take too much.

That's not why. Acetaminophen is highly hepatoxic but it's only very delayed. It's added because they have a synergistic effect on pain relief.

I'm not suggesting the parent comment is correct, but I think they are implying that medicines are "spiked" with a chemical in order to deter recreational use, lest someone injure themselves.

Agree! Acetaminophen is very dangerous in overdose. I've seen lots of 20 year olds who get liver transplants after they OD (intentionally) on Tylenol. If they had taken Motrin instead they'd have been fine.

I have a close family member who works in pharma who regularly tells me there is no way the FDA would approve Tylenol over the counter if it was invented today.

> The United States produces more grapefruit than any other country, from Florida and now California as well (and elsewhere, though in smaller quantities).

Just a fwiw: Texas produces more Grapefruit than Florida or California. At least the past two seasons.

https://www.nass.usda.gov/Statistics_by_State/Florida/Public...

So uh, does this have any effect on THC uptake from cannabis edibles? Asking for a friend...

Yes, THC is also metabolized by the CYP3A4 enzyme that grapefruit inhibits

So, to be clear, you are saying that in this case the grapefruit would increase or decease the effect of the THC? In other words, to increase the effect of the cannabis, is it metabolites that we want to maximze, or the amount of unmetabolized free THC?

Yes, grapefruit would increase the effect, and you want to maximize the unmetabolized THC. (although the first metabolite 11-OH-THC is also active, the next metabolite THC-COOH isnt)

I once took too much acid and the hour I spent in the peak was too strong and took a lot out of me. By the time it passed, I felt ravenous hunger for the massive grapefruit I had in the fridge. About halfway through eating through it's succulent splendor, I had to set the fruit aside and lay down because I felt like I was peaking again.

Forgive me, I pictured your experience and it made me laugh. :-D

This is why grapefruits are such a recurring element in Fear & Loathing.

Myrcene helps THC cross the blood-brain barrier faster. It is found in over-ripe mango and as one of the terpenes in some varieties of cannabis.

> “But Zoloft, Viagra, Adderall, and others do not. “Currently, there is not enough clinical evidence to require Zoloft, Viagra, or Adderall to have a grapefruit juice interaction listed on the drug label,” wrote an FDA representative in an email.”

There is some pretty good research on the effects of grapefruit with viagra bioavailability.

https://pubmed.ncbi.nlm.nih.gov/11823754/

> “Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%).”

I wonder if anyone is asking the “longer than four hours” crowd about food intake...

I already have to deal with citrus names in different languages: pomelo in Spanish, toranja in Portuguese , grapefruit in English . This article added a bit to the confusion: pomelo comes from grapefruit?

From prior reading I've done, grapefruit was cultivated by crossing pomelo with smaller, more bitter citrus. Here, the wikipedia says it was with a sweet orange [1]

1. https://en.wikipedia.org/wiki/Grapefruit

The article actually explains this quite well.

Although “pomelo” in Spanish translates (typically) to “grapefruit”, “pomelo” in English refers to another fruit, that is like a grapefruit.

Turns out English is surprisingly rich when it comes to describing citrus. The citrus family hybridizes very easily, so every planted seed will give you a “new species” with a unique cultivar. English appears to have assigned more unique names to citrus than the other two languages I know (Italian and Spanish)

Citrus names across languages are a mess. For example, citron is the English name for one of the base fruits, which after several hibridisation steps with other fruits results in the lemon. Dutch name for lemon? Citroen. In French it's citron. The French word for the English citron is cédrat. Sukade in Dutch.

The Dutch for pomelo is pompelmoes, while the pomelo is a hybrid between the pompelmoes and the grapefruit, and is called shaddock in English according to the Dutch Wikipedia.

Mexican Spanish (might be a broader phenomenon) is another fun one. Limes are limónes and lemons are limas. So sopa de lima is chicken soup with lemons, not limes. However, this is how they map those terms to the varieties present in America. The actual lima is a citron x lemon variety that is not widely cultivated, and is maybe best substituted by Key limes. Which explains why the Mexican stores around me seem to always carry Key limes in addition to the Persian limes!

"true" limes (by which I mean, the Mexican limon is the species most often referred to by variations on "lime" in other places) have become fairly common in American groceries.

Which is fortunate, they're tastier than the lime-lemon "Persian" lime hybrid, whose main virtue seems to be size.

Key limes are the best though, I wish they would show up in my local grocery more often.

Is complicated, there are TWO "grapefruits", not one.

Pomelo and grapefruit is not exactly the same term but is used as synonym often in different languages.

Like a primary color (RBG), pomelo can be thought of like a primary citrus.

Pomelo is a citrus fruit that has been mixed with other citrus fruits to make new varieties, like grapefruit.

And in French grapefruit is pamplemousse, and pomelo traditionnally refer to the pink grapefruit, which is actually a slight variant. Actual pomelos always come from China, they have a very thick rind (2 cm or more) and have a taste and texture of their own (they're very dry) which is quite pleasant.

See https://en.wikipedia.org/wiki/Pomelo

> This article added a bit to the confusion: pomelo comes from grapefruit?

Other way around. In english, the Pomelo is "Citrus maxima", one of the "ancestral" citrus varieties, which is very large with a very thick rind.

The grapefruit is (believed to be) a hybrid of the pomelo and the regular (sweet) orange, which is itself a hybrid of some sort (a much removed descendant of pomelo and mandarin).

If grapefruit causes the bio availability of a drug 10x stronger, it makes sense to be to prescribe 1/10* the amount of a drug with a shot of grapefruit juice. Seems like a good way to make drugs more economical.

* I'm assuming the active ingredient in drug is in the 10mg+ range. The way to get the accuracy needed from 1mg to 100ug sounds nontrivial to me.

For most drugs the economics aren't about the cost of producing the chemicals but all of the R&D behind the companies. Whether it's 10mg or 1000mg I don't think it's typically a material part of the cost.

Why would a patient or doctor care about that?

Pills have more things than the active compound. Taking less may reduce any hypothetical secondary collateral effects from those substances, so it could be useful to explore it at least.

On the other hand, taking just a tenth part of a pill would be not easy to measure. Specially if you need to take the pills often. Sometimes you would take 1/10, other 3/10 or 1/20. That could be a recipe for problems.

Ok, I agree with the first paragraph (it’s a point I did not think about).

The second point is a weak one as you must be quite special to consciously decide on changing the prescribed dose of the pill without buying scales to measure the dose (although I agree these costs quite a lot).

The article doesn't say it, but there are some drugs that need processing, by the cytochrome P450 or the CYP3A4 pathway that grapefruit knocks out, in order to become active. Those drugs will lose their effect. Also, the same process may be part of the pathway that removes the precursor chemicals from the bloodstream, so those build up, potentially to toxic levels; you get the overdose without even the dose.

Once, in Switzerland, I found a Lindt chocolate bar with dried grapefruit in it. I have never been able to find another. I wonder now if there are regulations about grapefruit ingredients in some countries.

But I really love grapefruit. Haribo makes yellow and pink grapefruit gummi candy that is getting hard to find. I would really like to know if they have fouranocoumarins in them, but don't know of any way to find out.

A web search turns up quite a few results for those lindt chocolate bars with grapefruit.

To find that out you could buy a gas chromatography machine, but I'm not sure if they sell home appliance versions of the equipment.

This paper has some interesting reading on where the various citrus varieties evolved from

Genomics of the origin and evolution of Citrus https://www.nature.com/articles/nature25447/ (Open Access)

The drug-discovery venture I lead goes into some detail on grapefruit, hesperidin, and naringin in context of drug interactions at the end of this article in Medium’s An Idea publication (just scroll to the graphic from the FDA):

https://medium.com/an-idea/enter-flavonoids-f42662810c11

Conventionally was thought that the main culprit was bergamotin; but subsequent research showed that naringin (citrus in general but grapefruit especially) and hesperidin (citrus in general - orange, lime, lemon) have their own important interactions with drug-metabolizing enzymes.

[Here is a link straight to the academic paper on naringin / hesperidin on the human OATP1A2 human medicine-processing enzyme (so you can skip having to find the link in the above Medium article): https://pubmed.ncbi.nlm.nih.gov/17301733/ ]

Flavonoids are a unique class of plant-derived compounds; They can bind a lot of things - in some cases that's bad according to some med chemists, and some cases its good according to other med chemists . . .

I wonder if this is at all related to the common pairing of citrus fruits with psychedelic drugs. A lot of people recommend eating an orange or drinking orange juice when you take LSD, and a lot of people recommend using lemons to enhance psilocybin mushroom trips. Maybe grapefruit would pair even better with these drugs.

Grapefruit juice also has drug interactions with opiates and (I think) anti depressants, amongst other things.

The lemon-tek method of consuming psilocybin mushrooms isn’t related to this. Acidic conditions speed up the conversion of psilocybin into psilocin. This normally happens in your stomach, the lemon-tek method just does externally. This causes the overall experience to be shorter, but more intense. Psilocin also doesn’t appear to be metabolized by the enzymes that grapefruit inhibits.

source?

The wikipedia article for Psilocybin has all of the above.

>Psilocybin [...] is a prodrug that is converted into [...] psilocin [...] This chemical reaction takes place under strongly acidic conditions

And for metabolism

>Psilocin is broken down by the enzyme monoamine oxidase [...] Some psilocin is not broken down by enzymes and instead forms a glucuronide [...] Psilocin is glucuronated by the glucuronosyltransferase enzymes UGT1A9 in the liver, and by UGT1A10 in the small intestine

Certainly reminds me of the Kool Aid in "Electric Kool Aid Acid Test"

It's definitely on the label of my daily medication (in the UK), but it was interesting to see how the interaction seems to be fairly specific to grapefruit. Do either of the ancestor species have a similar effect?

I do wonder if there are other dietary/medication interactions that we simply haven't spotted, but which could allow for lower doses of medication (potentially with fewer side effects, if the effect was on one active component) or simply avoid some side effects altogether.

From the article:

> This interaction, by the way, seems to affect all of the bitter citruses—the ones that inherited the telltale tang from the pomelo. Sour orange. Lime, too. But it’s unlikely that anyone would drink enough sour orange or lime juice to have this effect, given how sour it is. Grapefruit, on the other hand, is far more palatable in large doses.

I wonder what the concentrations are in bottled lime juice, which is easier to consume than fresh lime.

Does grapefruit's affect have anything to do with gut bacteria? That is, (good) bacteria plays a key role in digestion. Does this factor in anywhere?

I’m wondering, why not take advantage of this and add the grapefruit furanocoumarins to drugs to make smaller doses more effective?

It would be worth big pharma looking further into. I fear however they'll identify that blood serum levels of an ingested drug are variable enough as it is due to the uniqueness of humans, that actively modulating humans ability to process exogenous chemicals is a recipe for disaster. Maybe they'll even get it close to right for Drug A, but what about Drug B that any given patient is concomitantly taking?

People often take multiple prescription medications, doing this might complicate things. The cytochrome P450 enzymes help metabolize a very wide range of compounds.

Because it would increase the number of medications that interact with each other. E.g. you're taking medications A and B, but now A and B come with the potentiating compounds in the pills. So taking both of them could be dangerous. You to go to the hospital and they need to give you C, but it would be dangerous because of the potentiator. It would also make medication management more difficult as people have to remember if they're taking the potentiated drug or not.

For those interested in a infographic on the chemistry of grapefruit, see [1]

[1] https://www.compoundchem.com/2014/03/07/why-does-grapefruit-...

What an interesting article. I am now very curious to try the mother fruits pomelo and citron.

Based on the description here, grapefruits potentiate drugs by reducing the effects of a digestive system enzyme that would otherwise destroy much of the drug. Does this mean that it only has impact when drugs are taken orally?

Pomelos are great, assuming you get one that has some sweetness to it. This can very much depend on your geography, as pomelos where I am are significantly more sour than they were in North America. Citrons are just gross.

Pomelo is sweet and acid, grapefruit is acid and not so sweet.

On the other hand, Citron is one of the best for to make candied citrus.

Pomelo has been my discovery of 2020 (pre-covid). They are the ideal fruit to eat while watching a movie in the evening. They are a lot of work as you need to peel through all three layers. Yet, you don't get dirty, and every now and again you get to eat a bit and it tastes like more.

Oranges and mandarins tend to get you dirty, and would still cause me to overeat.

Mandarins are a crapshoot. Sometimes you come away clean, especially if you are willing to bite the peel to start the peeling process.

Whether the wedges remain intact or not is the wildcard.

That depends on the type of mandarin

You can have clementines, satsumas, tangors and tangerines (plus a few strange complex hybrids). Some have adherent skins that can be messy to peel, the skins in other are extra easy to remove. Clementines are more sweet, tangors are more acidic so are still much appreciated. It depends on the group and cultivar

The fastest way to eat an orange is to treat it like a melon. Cut it in "watermelon portions" and just tear off the good parts with your teeth. Is not so messy for nails this way (but some juice can still drop).

The procedure is much more convenient if done with navel oranges (that are always seedless).

Seems like individual differences in bioavailability of drugs is a big problem in drug effectiveness. It seems that a procedure in which the amount getting to the bloodstream is measured, then adjusted (either by dosage increase, or bu supplementation with grapefruti) would be effective.

Instead of labeling drugs "do not take with grapefruit", how about using a different dosage for when you take it with grapefruit? Having more of the drug survive the stomach could be a good thing.

Or is that too unpredictable? More unpredictable than the effect of medication already is, I mean.

People would eat variable amounts of grapefruit and might not eat it every day. Medications also have the potential to become toxic and have other effects other than the therapeutic effect.

Can you imagine trying to explain this concept to an elderly family member? A blanket statement is easier to comprehend for the general population.

People DO take insulin where the med is adjusted based on the blood sugar, but this is often accompanied with diabetic education component that takes weeks to complete.

I have wondered though why no time release formulations increase longevity by including a small amount of the active ingredient of grapefruit. Likely due to the other interactions besides metabolism, like cardiac function.

Some antibiotics DO have adjuvants that prolong excretion. Examples are probenecid that was added to penicillin formulations to ensure there was enough supply. Imipenem (another antibiotic) is given with cilastin to reduce clearing of the drug by the kidney.

Patients get into trouble when their renal clearance is already poor from long-standing kidney disease, so the potential is there for the drug to build to a level where it exhibits effects beyond its therapeutic intent (ie toxicity).

The diabetes case is also most commonly accomplished with constant rapid testing. I don't think anybody loves grapefruit enough to bleed for it.

The article says that grapefruit wipes out cytochrome P450s for up to 12 hours.

Lets say I'm taking a medication which is impacted by this. If I were to take my meds and then have a grapefruit 12 hours later, would it impact the dosage of the medication?

Probably not. If the grapefruit is coming into your system 12 hours after the drug, the drug's already been processed by the P450 system. I think the odd coincidence here is that grapefruit is a "breakfast food" and thus people take it with their morning meds.

In college, I used to always order cocktails with grapefruit juice in the hope that I'd get more drunk for my money. Was I only benefiting from the placebo effect? Does grapefruit affect alcohol metabolism?

I don't think so, as alcohol is not degraded via P450 enzymes..

The first thing that struck me was "what about drugs that have little-to-no bioavailability after being ingested?" Would it make it possible to give drugs that are rejected for other reasons?

Any relation between furanocoumarins and coumarins? The latter is in cinnamon which I’ve read lately can be quite hazardous depending on the ingested amount.

It's hard to eat enough cinnamon to affect most people, but some are extra-sensitive to it. Apparently there is a lot less in the stuff labeled cinnamon and sold to Americans, which is actually not cinnamon at all, but cassia, a whole other species. The difference was understood in Europe in ancient times, so there is no excuse. Sometimes you can find the real stuff in the US labeled "Ceylon cinnamon". It's a darker red than cassia, which is unapologetically brown.

Real cinnamon tastes more like red cinnamon candy than cassia does. Americans are always mystified as to why cinnamon candy doesn't taste anything like the cinnamon they put in their pies.

In times of rationing, it was apparently not uncommon for grapefruit eaters to substitute added salt for the usual sugar to take some of the bitterness off.

CBD causes the same problems with drugs as grapefruit.

Do people eat that?

I see CBD edibles, oils, candies, etc... here in Oregon.

People ingest it, yes. my father-in-law preferred the effects of CBD over his hallucination medication, but couldn't take it because it interacted badly with his blood-pressure medication. He got some sort of mesh (sorry can't remember what) implanted which eliminated the use of his BP meds, and now he can replace his hallucination meds with CBD.

He's in his late 70s, and lived hard (enjoyed every minute of it, but still).

Would definitely like to hear more about this. Citations?

Did anyone else get hostile redirects when they went to this site? I did.

Why do I keep getting forwarded to a Norton Antivirus page?

Would grapefruit affect supplements as well?

https://www.scirp.org/journal/PaperInformation.aspx?PaperID=...

I believe there are low FC varieties in development, and already extant. TBH if you're taking statins, you should really reconsider - those things are terrible for you like the underlying symptoms you're trying to treat. Maybe just not eat like a hog?

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