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.
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.
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.
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.
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…
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.
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.
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.
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.
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'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"?
> 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)
> "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.
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.
> 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.
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.
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.
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%?
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.
> 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.
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.
> “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.
> “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 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?
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)
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.
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]
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.
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.
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):
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.
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.
> 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.
[+] [-] austincheney|5 years ago|reply
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
[+] [-] dundarious|5 years ago|reply
The extra information you provide is really interesting.
[+] [-] pattusk|5 years ago|reply
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
[+] [-] strogonoff|5 years ago|reply
As to soda, I struggle to imagine a soda that has any amount of juice worth taking into account…
[+] [-] savanaly|5 years ago|reply
[+] [-] Shivetya|5 years ago|reply
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.
[+] [-] carlmr|5 years ago|reply
[+] [-] MrYellowP|5 years ago|reply
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.
[+] [-] justusthane|5 years ago|reply
How much vitamin D were you taking?
How much time was there between taking vitamin D and drinking grapefruit juice?
[+] [-] et2o|5 years ago|reply
[+] [-] thw0rted|5 years ago|reply
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"?
[+] [-] sebmellen|5 years ago|reply
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)
[+] [-] pvaldes|5 years ago|reply
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.
[+] [-] jrs235|5 years ago|reply
I think blood oranges are sweet.
[+] [-] nkozyra|5 years ago|reply
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.
[+] [-] ycombinete|5 years ago|reply
Indeed! My wife literally eats lemons like they were oranges. Probably something for us to look out for!
[+] [-] dmurray|5 years ago|reply
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...
[+] [-] jalk|5 years ago|reply
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.
[+] [-] buddhiajuke|5 years ago|reply
[+] [-] jariel|5 years ago|reply
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 ...
[+] [-] gdrift|5 years ago|reply
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.
[+] [-] BelleOfTheBall|5 years ago|reply
[+] [-] sph|5 years ago|reply
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%?
[+] [-] mikestew|5 years ago|reply
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.
[+] [-] dwighttk|5 years ago|reply
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...
[+] [-] MisterTea|5 years ago|reply
[+] [-] hombre_fatal|5 years ago|reply
[+] [-] shawnz|5 years ago|reply
[+] [-] ficklepickle|5 years ago|reply
[+] [-] unknown|5 years ago|reply
[deleted]
[+] [-] headShrinker|5 years ago|reply
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%).”
[+] [-] forinti|5 years ago|reply
[+] [-] dzudndlf|5 years ago|reply
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)
[+] [-] wazoox|5 years ago|reply
See https://en.wikipedia.org/wiki/Pomelo
[+] [-] simtel20|5 years ago|reply
1. https://en.wikipedia.org/wiki/Grapefruit
[+] [-] pvaldes|5 years ago|reply
Pomelo and grapefruit is not exactly the same term but is used as synonym often in different languages.
[+] [-] GloriousKoji|5 years ago|reply
* 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.
[+] [-] Taek|5 years ago|reply
[+] [-] ncmncm|5 years ago|reply
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.
[+] [-] Lambdanaut|5 years ago|reply
[+] [-] copperx|5 years ago|reply
[+] [-] mkj|5 years ago|reply
Genomics of the origin and evolution of Citrus https://www.nature.com/articles/nature25447/ (Open Access)
[+] [-] ricksunny|5 years ago|reply
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.
[+] [-] ricksunny|5 years ago|reply
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 . . .
[+] [-] dfalzone|5 years ago|reply
[+] [-] mpettitt|5 years ago|reply
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.
[+] [-] thw0rted|5 years ago|reply
> 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.
[+] [-] chiefalchemist|5 years ago|reply
[+] [-] surround|5 years ago|reply
[+] [-] sohkamyung|5 years ago|reply
[1] https://www.compoundchem.com/2014/03/07/why-does-grapefruit-...