Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy(societyforscience.org)
societyforscience.org
Modification of acetaminophen to reduce liver toxicity and enhance drug efficacy
https://www.societyforscience.org/regeneron-sts/2025-student-finalists/chloe-lee/
159 comments
It's always weird to me that acetaminophen has such a low therapeutic index, like in order to get enough for it to do anything, you're also on the verge of liver failure (especially if you also drink alcohol). Also it just doesn't work super well in my personal experience --- I hardly feel anything when I take it. And yet it's one of the most commonly taken medicines worldwide.
I'm a big fan of it in terms of efficacy; does wonders for headaches as well as joint aches.
My concern is about the relatively recent findings about potential Alzheimer risk [1]:
> During a median follow-up of 12.3 years, 6407 (3.0%) participants developed new-onset all-cause dementia. Participants who regularly used paracetamol had a significantly higher risk of new-onset all-cause dementia (adjusted HR, 1.18; 95%CI: 1.10-1.26), compared with non-users. However, there was no significant association between regular use of ibuprofen and new-onset all-cause dementia (users vs. non-users; adjusted HR, 1.06; 95%CI: 0.97-1.16).
I don't follow the research closely enough to know if this is reliable evidence, but there are other studies showing the same thing.
Paracetamol also well known as mood-altering, apparently inhibiting empathy [2], which may be part of why it has an analgesic effect. That isn't as scary on a personal level, but imagine a society full of millions of people on paracetamol whose ability to feel empathy has been blunted.
[1] https://pubmed.ncbi.nlm.nih.gov/37633120/
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC6455058/
My concern is about the relatively recent findings about potential Alzheimer risk [1]:
> During a median follow-up of 12.3 years, 6407 (3.0%) participants developed new-onset all-cause dementia. Participants who regularly used paracetamol had a significantly higher risk of new-onset all-cause dementia (adjusted HR, 1.18; 95%CI: 1.10-1.26), compared with non-users. However, there was no significant association between regular use of ibuprofen and new-onset all-cause dementia (users vs. non-users; adjusted HR, 1.06; 95%CI: 0.97-1.16).
I don't follow the research closely enough to know if this is reliable evidence, but there are other studies showing the same thing.
Paracetamol also well known as mood-altering, apparently inhibiting empathy [2], which may be part of why it has an analgesic effect. That isn't as scary on a personal level, but imagine a society full of millions of people on paracetamol whose ability to feel empathy has been blunted.
[1] https://pubmed.ncbi.nlm.nih.gov/37633120/
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC6455058/
I'm pretty sure ibuprofens risks are significantly higher than a 10-20% increased risk of dementia, it gives significantly increased risk of strokes iirc
I thought NSAIDs thinned blood more like apsirin and gave aneurysm risk instead of stroke, and the big risk was stomach bleeds.
NSAIDs are COX inhibitors which inhibit either COX-1, COX-2, or both.
COX-1 is involved in the gastric mucosa, among other roles, which is why blocking it can cause stomach bleeding.
COX-2 is involved in maintaining the endothelium of blood vessels, and can increase stroke and infarction risk by stiffening and degrading the lining of the blood vessels over time.
Studies are a bit conflicting regarding whether blocking COX-1 or COX-2 is safer, as there seems to be downsides to both, and the difference in risk isn't that clear.
COX-1 is involved in the gastric mucosa, among other roles, which is why blocking it can cause stomach bleeding.
COX-2 is involved in maintaining the endothelium of blood vessels, and can increase stroke and infarction risk by stiffening and degrading the lining of the blood vessels over time.
Studies are a bit conflicting regarding whether blocking COX-1 or COX-2 is safer, as there seems to be downsides to both, and the difference in risk isn't that clear.
"Therapeutic index" is a strange number to worry about. Those index scores are the balance between efficacy and toxicity.
Acetaminophen is an effective analgesic, just toxic in large doses. It's perfect for lower intensity pain. It's non-addictive, doesn't have long term issues like NSAIDs. It's popular for a reason.
Acetaminophen is an effective analgesic, just toxic in large doses. It's perfect for lower intensity pain. It's non-addictive, doesn't have long term issues like NSAIDs. It's popular for a reason.
My family always had boxes of it around the place when I was growing up. Never really had much use for pain killers. But when I was in my early 20s, no money, not looking at myself, I cracked a tooth in half and it took a few days to see the dentist. It was excruciating. First thing I did, take paracetamol (our name for acetaminophen). It did absolutely nothing. The pain was like a lightning bolt from tooth to brain. After another 30 minutes, I couldn't handle it any more, went to the pharmacy and got aspirin. That worked within 20 minutes.
I have never taken acetaminophen since then. If it's a low intensity pain, then I can handle it myself. If I need actual pain relief I'll use an NSAID.
Finding out later that paracetamol dosage is super close to overdose, and how it actually kills you... That put the tin hat on it.
I have never taken acetaminophen since then. If it's a low intensity pain, then I can handle it myself. If I need actual pain relief I'll use an NSAID.
Finding out later that paracetamol dosage is super close to overdose, and how it actually kills you... That put the tin hat on it.
Neuropathic pain (which dental pain mostly is) is poorly handled.
I agree, paracetamol isn't perfect for every type of pain. NSAIDs help relieve pressure and can help, and opioids can waffle-stomp most pain but only for a little while and with dire risks of dependency, but for-purpose drugs like gabapentin are usually a lot more effective at blocking even high intensity neuropathic pain. Unlike NSAIDs, you can take them long term without needing a cocktail of PPIs to keep your stomach from imploding, and they're non-addictive.
I agree, paracetamol isn't perfect for every type of pain. NSAIDs help relieve pressure and can help, and opioids can waffle-stomp most pain but only for a little while and with dire risks of dependency, but for-purpose drugs like gabapentin are usually a lot more effective at blocking even high intensity neuropathic pain. Unlike NSAIDs, you can take them long term without needing a cocktail of PPIs to keep your stomach from imploding, and they're non-addictive.
Super close may be an exaggeration but could certainly be voted “most likely analgesic to let you take an intentional overdose”.
The effectiveness varies a lot. For me it works great, several other people I know get no effects at all from taking safe doses and of course excess doses are potentially extremely dangerous, extremely fast - about 2.5x the usual maximum dose causes liver failure in some people, that's barely more than "Oops, I already took that and I forgot" from a nasty death.
If it was discovered tomorrow rather than last century, it would never get OTC approval, because while for some people (like me) it's useful, the dangers are too high, so they'd definitely make it prescription-only. I'd probably still come back from any surgery with a bag of paracetamol because it's cheap and the surgeons can prescribe it to somebody it works on without worrying (it's not like an opioid, nobody is going to get unnecessary surgery so as to secure more paracetamol) but it would not be in cold & flu meds if they hadn't found it last century when they were more lax about safety.
[Edited to insert crucial omitted "not"]
If it was discovered tomorrow rather than last century, it would never get OTC approval, because while for some people (like me) it's useful, the dangers are too high, so they'd definitely make it prescription-only. I'd probably still come back from any surgery with a bag of paracetamol because it's cheap and the surgeons can prescribe it to somebody it works on without worrying (it's not like an opioid, nobody is going to get unnecessary surgery so as to secure more paracetamol) but it would not be in cold & flu meds if they hadn't found it last century when they were more lax about safety.
[Edited to insert crucial omitted "not"]
It’s cheap, too.
It’s unfortunate that it doesn’t work for you. Personally, I’ve never experienced a pharmaceutical that worked so reliably and predictably. It would bring a fever down in my kids when they were young without fail in about 25 minutes.
To be fair though I really haven’t been involved with more than a handful of medications. I’m sure there’s many that work very crisply.
To be fair though I really haven’t been involved with more than a handful of medications. I’m sure there’s many that work very crisply.
Similar to you it is incredible at bringing down fever in my kid. I've seen my kid go from whimpering looking like death, to be crawling about playing happily again in half an hour. With the behaviour change tracking with her temperature coming down.
As an adult using it as a pain killer it has been ineffective.
As an adult using it as a pain killer it has been ineffective.
For me I’ve found it works incredibly well at killing a headache or outright stopping a scintillating migraine (especially when combined with caffeine). But for body aches and pains I also find it doesn’t do a whole lot, especially compared to ibuprofen.
Calpol in the UK, paracetamol for children in liquid form (which is British name for acetaminophen) works wonders for kids with a fever. I'm not exaggerating when I say that every doctor I've seen with my kids has said not to withhold it as it really helps with fever.
Two tablets work great for me for headaches but results do vary. The danger zone for liver damage is roughly 14 tablets taken all at once. (Less if you've been drinking.) From what I'm told, acetaminophen overdose is quite an unpleasant way to die.
You die from liver failure. Which is a horrible way to die. You’re bleeding and clotting at the same time. Your abdomen swells with fluid. Then your legs and your whole body. Your skin turns yellow and you’re itching constantly. You become increasingly confused and violent. Infections start brewing in that pool of fluid in your abdomen.
I am going to cancel my internet subscription...
You should sign up for Nautilus. Monthly compact discs mailed to your door containing 650MB of assorted interactive multimedia. It was the original broadband (with very large packet size.)
(You might need a Time Machine first)
(You might need a Time Machine first)
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The maximum single dose of paracetamol is 1000 mg, and four doses (4000 mg) in 24 hours.
Any more and it's liver damage.
Any more and it's liver damage.
I will respond here with links, because my comments regarding NAC and silymarin are getting down-voted.
https://emedicine.medscape.com/article/820200-treatment - Treatment for liver damage is NAC (N-acetylcysteine) which is available as a supplement.
> N-acetylcysteine (NAC) is the mainstay of therapy for acetaminophen toxicity
https://www.ncbi.nlm.nih.gov/books/NBK537183/
Again, NAC is readily available without prescription.
Additionally, see https://www.medscape.com/viewarticle/422884 for Silymarin (which is found in Milk Thistle).
That said, do not exceed the maximum dose. Try ibuprofen, diclofenac, or whatever else, but they are not without risks either. For the record, acetaminophen is the only painkiller you can take on an empty stomach without it causing any GI issues.
https://emedicine.medscape.com/article/820200-treatment - Treatment for liver damage is NAC (N-acetylcysteine) which is available as a supplement.
> N-acetylcysteine (NAC) is the mainstay of therapy for acetaminophen toxicity
https://www.ncbi.nlm.nih.gov/books/NBK537183/
Again, NAC is readily available without prescription.
Additionally, see https://www.medscape.com/viewarticle/422884 for Silymarin (which is found in Milk Thistle).
That said, do not exceed the maximum dose. Try ibuprofen, diclofenac, or whatever else, but they are not without risks either. For the record, acetaminophen is the only painkiller you can take on an empty stomach without it causing any GI issues.
Acetylcysteine isn't magic though.
It needs to be administered within 12h and 5% will have a severe anaphylactic-type reaction with risk of respiratory arrest. And the liver can still have been irreparably damaged due to other factors.
In the context of this being a miserable way to kill yourself, it's absolutely awful because there is very much a cut off point where you will still be suffering immeasurable pain and no amount of NAC will save you.
It needs to be administered within 12h and 5% will have a severe anaphylactic-type reaction with risk of respiratory arrest. And the liver can still have been irreparably damaged due to other factors.
In the context of this being a miserable way to kill yourself, it's absolutely awful because there is very much a cut off point where you will still be suffering immeasurable pain and no amount of NAC will save you.
I did not say it is magic. At any rate, silymarin is actually "magic". It may help you regenerate parts of your liver. See the link I mentioned.
Ultimately, what one needs to do is just... not consume high amounts, or too frequently.
Ultimately, what one needs to do is just... not consume high amounts, or too frequently.
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It's terrible that you are counting in tablets instead of actual amount of acetaminophen
It's for this reason in the UK paracetamol (as we call acetaminophen) is only ever manufactured to 500mg tablets. I don't know if that is global.
Tylenol markets a 650mg Extended Release for Arthritis and Joint Pain:
https://www.tylenol.com/products/arthritis/tylenol-8hr-arthr...
It is effective for me for general analgesia.
Trigger warning for self harm.
The real tragedies with acetaminophen are "cry-for-help" situations where someone thinks it is the same as aspirin, and swallows a handful, perhaps washing it down with alcohol. What might have been a suicide hesitation mark becomes an entry on a liver transplant list - if they are lucky. If you have children, make sure they know which one can be deadly, especially before going off to college.
Trigger warning for self harm.
The real tragedies with acetaminophen are "cry-for-help" situations where someone thinks it is the same as aspirin, and swallows a handful, perhaps washing it down with alcohol. What might have been a suicide hesitation mark becomes an entry on a liver transplant list - if they are lucky. If you have children, make sure they know which one can be deadly, especially before going off to college.
Here in Sweden, a carton of 10 × 500 mg is the most you can find without a subscription. (Boxes of twice that amount is supposed to exists but I've never seen it)
Two years ago, I was prescribed the maximum dosage: 2 × 500 mg every six hours for a couple of months. Because it wears off more quickly than that, I tried to reduce it to one and a half pill more often but that wasn't enough to have any effect. Caffeine is supposed to reinforce the effect, but of course I had to avoid that to sleep.
I also got it as intravenous liquid at a time when I couldn't swallow.
Two years ago, I was prescribed the maximum dosage: 2 × 500 mg every six hours for a couple of months. Because it wears off more quickly than that, I tried to reduce it to one and a half pill more often but that wasn't enough to have any effect. Caffeine is supposed to reinforce the effect, but of course I had to avoid that to sleep.
I also got it as intravenous liquid at a time when I couldn't swallow.
> Here in Sweden, a carton of 10 × 500 mg is the most you can find without a subscription. (Boxes of twice that amount is supposed to exists but I've never seen it)
That ain't much, I don't think I've seen boxes with that little around here. Normal packaging is 30~40, and you can get larger boxes, all without a script.
Are the boxes that small because sweden tends to use an other analgesic as primary culturally e.g. aspirin or ibuprofen and paracetamol is for more exceptional situations?
> Caffeine is supposed to reinforce the effect, but of course I had to avoid that to sleep.
If the goal was pain relief, you can combine ibuprofen and paracetamol. They can be staggered or taken together (in which case there's less duration coverage but some evidence that the combination works better than either separately).
That ain't much, I don't think I've seen boxes with that little around here. Normal packaging is 30~40, and you can get larger boxes, all without a script.
Are the boxes that small because sweden tends to use an other analgesic as primary culturally e.g. aspirin or ibuprofen and paracetamol is for more exceptional situations?
> Caffeine is supposed to reinforce the effect, but of course I had to avoid that to sleep.
If the goal was pain relief, you can combine ibuprofen and paracetamol. They can be staggered or taken together (in which case there's less duration coverage but some evidence that the combination works better than either separately).
There are almost no situations were taking the recommended dosage of acetaminophen is harmful. It's either useless (won't help for a skin rash for example) or has positive effects.
There absolutely ARE situations where ibuprofen should not be used (kidney, infections, others), even at the usual dosage.
Hence I believe that it's a terrible idea to write on the internet "they can be staggered or taken together" as if they had a simimar safety profile
There absolutely ARE situations where ibuprofen should not be used (kidney, infections, others), even at the usual dosage.
Hence I believe that it's a terrible idea to write on the internet "they can be staggered or taken together" as if they had a simimar safety profile
> Are the boxes that small because sweden tends to use an other analgesic as primary culturally e.g. aspirin or ibuprofen and paracetamol is for more exceptional situations?
No, I'd say paracetamol is the most common. I think there was an increase in teenagers that tried to overdose on it to commit suicide some years ago. You could easily get 1000mg pills before that.
No, I'd say paracetamol is the most common. I think there was an increase in teenagers that tried to overdose on it to commit suicide some years ago. You could easily get 1000mg pills before that.
Ibuprofen, naproxen and acetylsalicylic acid are also common.
I prefer acetaminophen due to the main metabolite being a reuptake inhibitor of CB-active transmitters and I don't drink. I take maybe two-four grams per year, so your 40-pill box would last for a decade.
I prefer acetaminophen due to the main metabolite being a reuptake inhibitor of CB-active transmitters and I don't drink. I take maybe two-four grams per year, so your 40-pill box would last for a decade.
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FYI in france no box is allowed to contain more than 1g. And in theory pharmacist should not accept selling more than 1 box, they tend to do though.
Can't put a source but I had lessons explaining that the US had insane rates of tylenol suicide, and that are apparently correlated with the size of boxes sold otc. Years ago many countries including france put a limit on the quantities sold at once and the suicides plummeted. The US didn't because of lobbies or something.
So sad and obvious.
Can't put a source but I had lessons explaining that the US had insane rates of tylenol suicide, and that are apparently correlated with the size of boxes sold otc. Years ago many countries including france put a limit on the quantities sold at once and the suicides plummeted. The US didn't because of lobbies or something.
So sad and obvious.
1000mg is readily available around here, and although 500s are splittable you’ll find the odd 200~250 (mostly for children I assume).
Do you guys have liquid forms, especially for children where the dosage is, obviously, entirely up to you?
One memory I have of visiting our U.S. head office with a bunch of UK people was the “we have to get to Target because they sell Tylenol in ungodly quantities.” And I thought bottles of 200 pills felt ridiculous up here in Canada.
One memory I have of visiting our U.S. head office with a bunch of UK people was the “we have to get to Target because they sell Tylenol in ungodly quantities.” And I thought bottles of 200 pills felt ridiculous up here in Canada.
Yeah, you can get lower doses. It turns out I was wrong and you can get 1g, but my understanding is it's not used in routine healthcare (for obvious reasons). https://bnf.nice.org.uk/drugs/paracetamol/medicinal-forms/#o...
I'd be interested to know if I'm wrong though.
I'd be interested to know if I'm wrong though.
It feels like it’s quite simply a sensible approach to normalize as much as possible.
In france the usual dosage most of the time is 1g
You can get 1000mg tablets but only if prescribed by a doctor
My doc wouldn't prescribe 1000s for me. I took two 600s (severe pain was kept at bay).
I don’t think it is. Many combinations available in the USA.
It's not possible to state an absolute toxic dose in milligrams for everybody because it depends on things like your body mass, the preexisting condition of your liver, whether other liver-damaging drugs are on board, etc.
In my case I was talking about 500 mg tablets which are commonly branded in the US as "Extra Strength Tylenol."
The point I was trying to make is that the deadly dose divided by the therapeutic dose for acetaminophen can be as small as 7. This is a much smaller ratio than for most other common over-the-counter drugs. There's not much room for error with acetaminophen.
In my case I was talking about 500 mg tablets which are commonly branded in the US as "Extra Strength Tylenol."
The point I was trying to make is that the deadly dose divided by the therapeutic dose for acetaminophen can be as small as 7. This is a much smaller ratio than for most other common over-the-counter drugs. There's not much room for error with acetaminophen.
> It's not possible to state an absolute toxic dose in milligrams for everybody because it depends on things like your body mass, the preexisting condition of your liver, whether other liver-damaging drugs are on board, etc
Well yes it is possible to define an absolute toxic dose. 100 grams is an absolute toxic dose of acetaminophen in humans, 8294 tablets is not a dose.
Well yes it is possible to define an absolute toxic dose. 100 grams is an absolute toxic dose of acetaminophen in humans, 8294 tablets is not a dose.
I take it mostly as an anti-pyretic (fever reducer). For which it is extremely effective. It's my drug of choice for colds, flu, etc.
Well, it doesn't work for high fever (> 39-40 Celsius). For that, I alternate Ibuprofen and sodium metamizole every 4 hours.
For pain release, paracetamol it's very modest. Some effect for light head pain, zero for strong pain. Zero effect for strong back pain. Ibuprofen works better in all these cases but comes with stomach damage if taken for long.
For pain release, paracetamol it's very modest. Some effect for light head pain, zero for strong pain. Zero effect for strong back pain. Ibuprofen works better in all these cases but comes with stomach damage if taken for long.
Paracetamol is nicely synergic with all known painkillers. For example prescribing it with morphine leads to less morphine consumption.
Also: it's a terrible rule of thumb to take an NSAID routinely for general infectious symptoms like fever.
Also: it's a terrible rule of thumb to take an NSAID routinely for general infectious symptoms like fever.
Prescribing cannabis for pain also leads to less morphine consumption.
The safety profile of paracetamol is orders of magnitudes higher ghan cannabis though. It is still one of the, if not the, most heavily used and appreciated drug and can be taken at any age
That is untrue. Did you read the OP article? Just 10 standard 500mg tablets of paracetamol in 24h will cause irreversible liver damage.
It’s the exact opposite of what you claim. Cannabis is orders of magnitude less destructive to the body than paracetamol.
If you honestly believe what you wrote, you need to check your sources. There is a lot of drug war propaganda still out there.
It’s the exact opposite of what you claim. Cannabis is orders of magnitude less destructive to the body than paracetamol.
If you honestly believe what you wrote, you need to check your sources. There is a lot of drug war propaganda still out there.
indeed I have not been specific enough: I meant "at therapeutic dosage". Thank you for keeping me in check!
Acetaminophen indeed has a shitty therapeutic index and cannabis in any (natural) form has basically no acute toxicity.
But i'd take 1g of acetaminophen daily for the rest of my life starting at age 1 instead of taking 1 cannabis joint equivalent every day. And that's even if we're talking edible form or vaping (i.e. not considering tars).
What about you?
Acetaminophen indeed has a shitty therapeutic index and cannabis in any (natural) form has basically no acute toxicity.
But i'd take 1g of acetaminophen daily for the rest of my life starting at age 1 instead of taking 1 cannabis joint equivalent every day. And that's even if we're talking edible form or vaping (i.e. not considering tars).
What about you?
But how many cases of poisoning occur each year?
“56,000 emergency department visits and 2600 hospitalizations, acetaminophen poisoning causes 500 deaths annually in the United States” -Acetaminophen Toxicity
Suneil Agrawal; Brian P. Murray; Babak Khazaeni. https://www.ncbi.nlm.nih.gov/books/NBK441917/
That’s a lot. I keep forgetting how many idiots are in the world.
Some of those are probably intentional suicide attempts. What’s the maximum number of tablets for one purchase? Sweden has it regulated down to 14, because that’s just enough to not cause permanent damage in a depressed teenager.
Some of those are probably intentional suicide attempts. What’s the maximum number of tablets for one purchase? Sweden has it regulated down to 14, because that’s just enough to not cause permanent damage in a depressed teenager.
My understanding is it isn’t so much people being idiots but that acetaminophen is in many products making it easy to overdose on when you are sick.
https://www.fda.gov/consumers/consumer-updates/dont-overuse-...
https://www.fda.gov/consumers/consumer-updates/dont-overuse-...
Ah, I see,,, Wikipedia tells us:
“While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[106] […] Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.[110] The overdose risk may be heightened by frequent consumption of alcohol.[111]“
So, combination drugs being used recreationally, yeah I guess I can believe that would lead to not keeping track of how much paracetamol you took today. And especially over time.
I figured it would be pretty hard to accidentally exceed 4000 mg in a day, but if you’re high on some stronger painkillers, which you’re developing some tolerance for, then it’s easy to just keeping taking more than you did last time.
“While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[106] […] Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.[110] The overdose risk may be heightened by frequent consumption of alcohol.[111]“
So, combination drugs being used recreationally, yeah I guess I can believe that would lead to not keeping track of how much paracetamol you took today. And especially over time.
I figured it would be pretty hard to accidentally exceed 4000 mg in a day, but if you’re high on some stronger painkillers, which you’re developing some tolerance for, then it’s easy to just keeping taking more than you did last time.
Um. I could go to Walmart or Target and buy pounds of it.
> I hardly feel anything when I take it.
Would that not make it a very effective pain killer? /s
But seriously - you are not supposed to "feel" a drug. Opiates work on a much different mechanism, and you do "feel" them, but that is also the same mechanism that make them so addictive. What you want is a drug that helps you manage pain and not be addictive.
Would that not make it a very effective pain killer? /s
But seriously - you are not supposed to "feel" a drug. Opiates work on a much different mechanism, and you do "feel" them, but that is also the same mechanism that make them so addictive. What you want is a drug that helps you manage pain and not be addictive.
acetaminophen should not be an OTC drug
The same website is also for the excellent Science News print magazine, which will ship you top notch science reporting right to your door. My father was a subscriber since, well, whenever blue LEDs were invented, because I recall reading about them in Science News.
Strong recommendation for any science-lover.
Strong recommendation for any science-lover.
Science News is a big part of my childhood. My stepdad's dad was a subscriber and every issue was handed down to us gently used. I have thousands of back issues.
Same. My highschool library in the 70’s had a subscription and I would read through them with relish.
She didn't even break the top 10 in this content: https://www.societyforscience.org/regeneron-sts/2025-student...
I'm impressed beyond words by these kids, though I think I'd give her the top prize. Watching my grandfather's final days taken away from him by the effects of morphine has always made me wish so much that we had much more effective non-narcotic painkillers
I'm impressed beyond words by these kids, though I think I'd give her the top prize. Watching my grandfather's final days taken away from him by the effects of morphine has always made me wish so much that we had much more effective non-narcotic painkillers
https://www.societyforscience.org/press-release/regeneron-is...
She's in top 4, awarded $600? I dunno this is a confusing layout/structure for how the program is conducted seeing as how the headline is $9m awarded.
She's in top 4, awarded $600? I dunno this is a confusing layout/structure for how the program is conducted seeing as how the headline is $9m awarded.
Reversible computing, materials science, genetic research… it’s insane that these kids are doing this level of work in high school.
They aren't doing it on their own. Most of these kids are working with established researchers who give them the shape of the project, as well as the tools and the expertise to accomplish it.
More recently the US scientific funding bodies have had summer programs for kids who wouldn't otherwise get that kind of access, but it's still the exception. It takes more than a summer to do this kind of work.
Edit: quick search for the father's name brings up this professor of biochemistry at UT Tyler:
https://www.uttyler.edu/directory/chemistry/lee-jiyong.php
and mom's name brings up this professor of pharmaceutical science:
https://www.unthsc.edu/college-of-pharmacy/eul-hyun-suh
I don't mean to take anything away from the kid or suggest that they don't work hard, are smart, etc., but these kinds of science fairs are fundamentally about access.
More recently the US scientific funding bodies have had summer programs for kids who wouldn't otherwise get that kind of access, but it's still the exception. It takes more than a summer to do this kind of work.
Edit: quick search for the father's name brings up this professor of biochemistry at UT Tyler:
https://www.uttyler.edu/directory/chemistry/lee-jiyong.php
and mom's name brings up this professor of pharmaceutical science:
https://www.unthsc.edu/college-of-pharmacy/eul-hyun-suh
I don't mean to take anything away from the kid or suggest that they don't work hard, are smart, etc., but these kinds of science fairs are fundamentally about access.
Thank god someone bothered to explain it to HN.
As someone getting a PhD at a top school and the first in my family to ever make it past high school I can assure you all these kids are raised from birth in a test tube by their parents.
As someone getting a PhD at a top school and the first in my family to ever make it past high school I can assure you all these kids are raised from birth in a test tube by their parents.
>these kinds of science fairs are fundamentally about access.
Completely agree there, which kind of brings me to a related thought:
One thing I do wonder is, if you look at a few hundred years ago a lot of the inventors in math, physics, engineering, were a tiny group of people with access to resources and education. You're always reading the same names.
It seems if we as a society could decide that science is more important to us, with 8 billion people on earth, if we gave more access, time and incentives to people we should be able to increase the amount of scientific results exponentially.
Completely agree there, which kind of brings me to a related thought:
One thing I do wonder is, if you look at a few hundred years ago a lot of the inventors in math, physics, engineering, were a tiny group of people with access to resources and education. You're always reading the same names.
It seems if we as a society could decide that science is more important to us, with 8 billion people on earth, if we gave more access, time and incentives to people we should be able to increase the amount of scientific results exponentially.
> if we gave more access, time and incentives to people we should be able to increase the amount of scientific results exponentially.
That's how ML research is - all you need is sufficient compute and some torrented training data. It gives rise to a new problem of drowning in the literature. I think we simply don't have the tooling and institutions to integrate simultaneous scientific advancements from any significant portion of the population.
That's how ML research is - all you need is sufficient compute and some torrented training data. It gives rise to a new problem of drowning in the literature. I think we simply don't have the tooling and institutions to integrate simultaneous scientific advancements from any significant portion of the population.
Meh. While I think the broad theme is fine (more access to education is generally good -- particularly when it comes to scientific literacy amongst the general public!), I think trying to encourage "research" in this way is largely pushing on a string. I can never figure out if this whole phenomenon of "science fairs" is just Kabuki theater for everyone involved, or if there's a core group of deeply deluded organizers who really believe that they're Making A Difference (tm) in scientific research, and are just completely blind to the career prospects of actual young scientists [1].
Time and experience has shown that "scientific innovation" cannot be made to happen faster by throwing more money at it, and a promising young person would be much better off by putting their talents to use doing something less random [2]. You can produce more good research in aggregate (maybe), but only in the same way that you can find more gold by crushing more rocks. Either way, you have to crush the rocks.
For example, the US government dramatically increased grad school funding through the 80s-2000s, and the primary outcome was an employment crisis amongst PhDs in the sciences. In the 40s-70s it was fairly straightforward to establish a career in research, but these days it's Hunger Games. I sort of fundamentally believe that the reason most science came out of the European aristocracy was not due to inequity, but because only someone well-off could devote their lives to something so erratic. Science is an avocation, not a vocation.
Science fairs and the like are a weird little subculture of college-application polishers, in part because nobody in their right mind actually wants to become a scientist. I think it's a safe bet that the young woman in this article ends up doing something more lucrative with her life (and good for her, if she does).
[1] Or even more cynically: the organizers do know, and are doing it because it builds their own careers.
[2] Or at least, with a higher alpha.
Time and experience has shown that "scientific innovation" cannot be made to happen faster by throwing more money at it, and a promising young person would be much better off by putting their talents to use doing something less random [2]. You can produce more good research in aggregate (maybe), but only in the same way that you can find more gold by crushing more rocks. Either way, you have to crush the rocks.
For example, the US government dramatically increased grad school funding through the 80s-2000s, and the primary outcome was an employment crisis amongst PhDs in the sciences. In the 40s-70s it was fairly straightforward to establish a career in research, but these days it's Hunger Games. I sort of fundamentally believe that the reason most science came out of the European aristocracy was not due to inequity, but because only someone well-off could devote their lives to something so erratic. Science is an avocation, not a vocation.
Science fairs and the like are a weird little subculture of college-application polishers, in part because nobody in their right mind actually wants to become a scientist. I think it's a safe bet that the young woman in this article ends up doing something more lucrative with her life (and good for her, if she does).
[1] Or even more cynically: the organizers do know, and are doing it because it builds their own careers.
[2] Or at least, with a higher alpha.
I suspect you're correct about basic / true research and discovery of 'the new'.
Also probably about that US Gov funding. I've heard it's more about knowing how to write a grant than it is about being worthy of getting one. Better direction, better active identification of candidates (instead of the passive system that's biased towards large players), better stability. All of those would help.
However, there's a _lot_ of stuff that would be within reach, were only enough mass manufacture involved to drive down the adoption cost and break through the catch 22. Many things only need for gathering the correct sort of people, giving them enough room to work on a clear goal, and seeing where things really are.
The big business problems with that are figuring out if the return is plausibly worth the investment, and feeding the baby long enough that it can become a working adult.
Also probably about that US Gov funding. I've heard it's more about knowing how to write a grant than it is about being worthy of getting one. Better direction, better active identification of candidates (instead of the passive system that's biased towards large players), better stability. All of those would help.
However, there's a _lot_ of stuff that would be within reach, were only enough mass manufacture involved to drive down the adoption cost and break through the catch 22. Many things only need for gathering the correct sort of people, giving them enough room to work on a clear goal, and seeing where things really are.
The big business problems with that are figuring out if the return is plausibly worth the investment, and feeding the baby long enough that it can become a working adult.
Eh. Even if 1 in 10000000 of the kids that do "science fairs" end up in "science research" with at least one "scientific innovation", and the rest of them make $$$ in industry, that's them working. This comment is asinine on too many levels to fully rebut.
Agreed, I don't believe the science fair will push research, but we need to lay the groundwork to build a society of researchers instead one of office drones, going through JIRA tickets.
The comment above yours is a really poor strawmanning attempt.
The comment above yours is a really poor strawmanning attempt.
> This comment is asinine on too many levels to fully rebut.
Thanks. I mean, it's not like I have direct experience with this stuff or anything, as one of those 9,999,999 who spent years of my life doing science, only to end up in industry.
Also, it's not like we would do better by skipping the years of science and going directly to the productive part, or that those (now grown up) "kids" are encouraged to continue circling the airstrip of life by the funding programs that are happy to pay postdoc salaries -- postdocs being the best kind of cheap, indentured labor -- to keep the dream alive just a little bit longer. After all, walking away from a PhD/postdoc(s) is only just a bit harder than chewing off your own leg to escape a bear trap.
It's clearly much better to waste the time of our smartest people by injecting false economic incentives into the system in an effort to socially engineer some kind of scientific command economy. Let's grind those rocks, and turn the cheap gravel into concrete to build glorious future!
Thanks. I mean, it's not like I have direct experience with this stuff or anything, as one of those 9,999,999 who spent years of my life doing science, only to end up in industry.
Also, it's not like we would do better by skipping the years of science and going directly to the productive part, or that those (now grown up) "kids" are encouraged to continue circling the airstrip of life by the funding programs that are happy to pay postdoc salaries -- postdocs being the best kind of cheap, indentured labor -- to keep the dream alive just a little bit longer. After all, walking away from a PhD/postdoc(s) is only just a bit harder than chewing off your own leg to escape a bear trap.
It's clearly much better to waste the time of our smartest people by injecting false economic incentives into the system in an effort to socially engineer some kind of scientific command economy. Let's grind those rocks, and turn the cheap gravel into concrete to build glorious future!
Resentment is inherently anecdotal, but nevertheless a data point.
The issue with your argument is that you’re conflating two different points on the academic pipeline by shitting on high school science fairs because of the post-doc hellscape further down the line.
The latter is a special case of low wage, dead-end jobs that are inherent to capitalism, which can more generally leave anyone paralyzed in a vicious grind loop. Improving this may require capitalistic reform such as UBI and increased housing supply, but is the human condition of the quest for satisfaction in one’s niche.
The former is exposure to future possibilities that could satisfy the constraints of economic and intellectual well-being, likely through incremental progress but with the potential for breakthrough in either realm.
The issue with your argument is that you’re conflating two different points on the academic pipeline by shitting on high school science fairs because of the post-doc hellscape further down the line.
The latter is a special case of low wage, dead-end jobs that are inherent to capitalism, which can more generally leave anyone paralyzed in a vicious grind loop. Improving this may require capitalistic reform such as UBI and increased housing supply, but is the human condition of the quest for satisfaction in one’s niche.
The former is exposure to future possibilities that could satisfy the constraints of economic and intellectual well-being, likely through incremental progress but with the potential for breakthrough in either realm.
> not due to inequity, but because only someone well-off could devote their lives to something so erratic.
Aren't those effectively the same thing? At least in the given context where society doesn't have the resources available for everyone to live like that.
Aren't those effectively the same thing? At least in the given context where society doesn't have the resources available for everyone to live like that.
Effectively the same in terms of distribution of outcome, perhaps, but it's a bit like saying that it's really unfortunate that poor people can't afford their own manicured gardens, peacock collection and garage full of antique race cars.
Only someone well off could devote the necessary resources to have a garage full of antique race cars.
People who can afford a garage full of antique race cars only exist due to inequity.
What's the difference between those statements? As far as I can tell the latter includes the former while adding an implicit assumption about total available resources versus total population.
Apologies if it seems like I derailed things. Your comment was interesting but I didn't understand (still don't) the significance of the distinction you went out of your way to draw there. That said, I think the trailing remark that "only someone well-off could devote their lives to something so erratic" really hits the nail on the head. Even today you can see elements of that, for example on certain parts of youtube. People with excessive expendable income occasionally do some really impressive stuff.
People who can afford a garage full of antique race cars only exist due to inequity.
What's the difference between those statements? As far as I can tell the latter includes the former while adding an implicit assumption about total available resources versus total population.
Apologies if it seems like I derailed things. Your comment was interesting but I didn't understand (still don't) the significance of the distinction you went out of your way to draw there. That said, I think the trailing remark that "only someone well-off could devote their lives to something so erratic" really hits the nail on the head. Even today you can see elements of that, for example on certain parts of youtube. People with excessive expendable income occasionally do some really impressive stuff.
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> It seems if we as a society could decide that science is more important to us, with 8 billion people on earth, if we gave more access, time and incentives to people we should be able to increase the amount of scientific results exponentially.
Yep, but we collectively decided that it is more profitable to put the best minds that manage to survive the education trials to either shaving off 0.0000001 cents of each financial transaction and to still make billions of dollars off of that or to sell ads so people get convinced they need to buy something. And those that get dropped along the education pipeline, we either let them stay on the road side and let them rot in poverty or we just use them as yet another source of labor ready to be exploited.
Yep, but we collectively decided that it is more profitable to put the best minds that manage to survive the education trials to either shaving off 0.0000001 cents of each financial transaction and to still make billions of dollars off of that or to sell ads so people get convinced they need to buy something. And those that get dropped along the education pipeline, we either let them stay on the road side and let them rot in poverty or we just use them as yet another source of labor ready to be exploited.
Science projects are a family affair, more often than not. Ask me how I know.
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> Watching my grandfather's final days taken away from him by the effects of morphine
Those were not prbly his final days. he was artifically kept alive by modern medicine. Those final days are not natural part of dying.
Those were not prbly his final days. he was artifically kept alive by modern medicine. Those final days are not natural part of dying.
I thought morphine didn't cause health damage to the human body apart from addiction and withdrawal symptoms.
Well it absolutely muddles your mind when you're on it and it causes constipation. It can also depress your respiratory system.
Not everyone experiences side-effects of opioids, in fact, they are not even THAT common. I do not experience euphoria, nausea, mental fog, or any sedation from ANY opioids. I experience constipation, but I am fine with that. Morphine might be more dulling (or foggy) than say, oxycodone, but it highly varies.
As for "depress your respiratory system", yeah, in high enough doses, or if you are especially sensitive to it.
Pharmaceutical opioids are pretty much safer than NSAIDs. The side-effects of NSAIDs are actually worse than the side-effect of opioids. You will not get ulcers, blood clots, stroke, heart issues, GI issues, and all sorts of other issues with opioids.
As for "depress your respiratory system", yeah, in high enough doses, or if you are especially sensitive to it.
Pharmaceutical opioids are pretty much safer than NSAIDs. The side-effects of NSAIDs are actually worse than the side-effect of opioids. You will not get ulcers, blood clots, stroke, heart issues, GI issues, and all sorts of other issues with opioids.
And it can make some people very nauseous.
Nobody discusses these mundane drawbacks when they talk about the evils of heroin addiction. When you're high, you puke and you cannot give a shit. Both figuratively and literally.
Nobody discusses these mundane drawbacks when they talk about the evils of heroin addiction. When you're high, you puke and you cannot give a shit. Both figuratively and literally.
Morphine, like all neurotransmitter drugs, affects the autonomic nervous system which can yield a cornucopia of unwanted and seemingly unrelated side effects. It’s a complex system that’s best treated with care.
Nurses in palliative care and hospice are well-known to generously administer morphine in increasing doses, because it eventually takes away all the pain and suffering (of the families and nurses).
That’s a controversial take
Which part? This is definitely a common practice.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4594093/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4594093/
Not just of the families and nurses.
.. and of the patient. Being in pain, especially constant pain, sucks major ass. People who haven't gone through that don't really know. You can't just ignore it so, in turn, it occupies every space in your brain. We don't realize how many functions we possess that require the precondition of some level of comfort.
As someone young with chronic pain issue but otherwise healthy , obviously increasing doses of opioids or really any opioids at all. This aspect of it occupying every space of your brain can be true in this case as well. It’s hard to compartmentalize and still go about your daily life while no one can see the anguish your in.
at least according to these people [0], you can overdose on morphine, same as any opiate or opioid. not sure their credentials but it makes sense; it's an opioid/opiate and those can cause respiratory depression.
[0]https://www.addictiongroup.org/drugs/opioids/morphine/overdo...
[0]https://www.addictiongroup.org/drugs/opioids/morphine/overdo...
Yeah its like any other opiod- it depresses respiratory function which can cause death but it isnt directly toxic to any organs like APAP is
Oh yeah morphine overdose will kill you dead because you will stop breathing and you won't even know it happened.
The instant antidote is Narcan which is available over the counter at pharmacies in some states.
The instant antidote is Narcan which is available over the counter at pharmacies in some states.
I'm pro-morphine as a controlled medicine for extreme pain and end-of-life. I've seen it work. I've had it post-surgery.
Fentanyl, my brother claims to be the best. It, too, can work wonders under a controlled environment.
Fentanyl, my brother claims to be the best. It, too, can work wonders under a controlled environment.
Fentanyl is pretty much better than morphine in every way. Less toxic, cheaper, and works better with less side-effects. Especially less histamine response, which is the body itching people get.
Unfortunately, it's tainted by illicit use. Damned to only be used in dire circumstances. It's a shame, really.
Unfortunately, it's tainted by illicit use. Damned to only be used in dire circumstances. It's a shame, really.
Journavx!
This would be incredibly cool if it works in reality and not just simulation. Remarkable that the author is just 17.
I’m not going to shit on it, nothing wrong with going into the family business - but it isn’t a complete coincidence that her dad is a PhD biochemist at UT Tyler.
Yeah, it's great to have kids excited about science, but at 17 it's extremely unlikely that she taught herself enough chemistry, organic chemistry and biochemistry to come up with this. She needs years more of college-level coursework. Essentially impossible without a biochemist in the family to guide her.
It never is, the winner of this competition is in astral radio telescopes.
Something tells me he didn't launch the satellite.
Something tells me he didn't launch the satellite.
With mentorship from Caltech and access to data from NASA’s NEOWISE mission, Matteo created a machine learning algorithm and compiled a groundbreaking database called VarWISE.
https://www.societyforscience.org/regeneron-sts/2025-student...
https://www.societyforscience.org/regeneron-sts/2025-student...
I knew someone who reached the final stage of one of these science fairs. Project was done at a lab in an Ivy League university over a couple of summers. Relative was a senior scientist at the lab and guided them every step of the way. Not to discount what these kids are doing, but the reality is that these science fairs have largely become a contest about how well your family is connected to science-fair-friendly research facilities and how good your presentation skills are. I mean, do we really think 17 year olds are out there doing human trials on novel cancer therapies? I’m sure there are some projects that are genuinely thought of and done by the students themselves, but looking at a lot of these PhD level research that are supposedly done as after school projects of high school kids, I can’t help but think the whole thing has become a bit of a farce.
And look at her mother -- https://profiles.unthsc.edu/profile/381 -- hmmm
Seeing articles like this is almost hard to read. My kids are very smart but this girl is 1000 times what they are doing. This girl is 1000 times what I am doing.
Maybe it is just imposter syndrome but sometimes I read articles like this and think I fell short in life. But I am also top of my peers at work and I am a health care provider and my clients all request me so I know I am doing good. Sometimes I just wonder what mark I will leave on this world.
My experience is that stuff like this isn't because someone is wildly smarter than everyone but because there are connections, support, and resources of some form.
I understand that and I do know that I am actually very intelligent and smart. Same for my children I mean damn I have already taught my 8 year old how to solder as good as a professional and am working on programming with him. And as a health care worker I can look after even the most difficult complex care clients where other health care workers struggle. That is what I am known for at work. But sometimes seeing literal teens doing things that seem so far ahead of me it
it's just a four step synthesis. with the help of a phd chemist you could probably learn the steps in three months, and if you put your mind to it you could learn the ochem in a year. this project is the culmination of at least a year-maybe even up to three-of work.
whats surprising is that parents let their kids do ochem at 17!! thats some toxic shit :). safety is why chemistry is not a super popular field at high school level science fairs.
whats surprising is that parents let their kids do ochem at 17!! thats some toxic shit :). safety is why chemistry is not a super popular field at high school level science fairs.
C'mon, who doesn't like their kids dusted with methylmercury?
I think the idea that one has to leave a mark on the world before one dies is overrated and not super useful.
First, what would such a mark be like for you? Is it something you could plausibly achieve with all the resources within your reach? Is it well-defined or is it nebulous? Is it likely to remain stable over the time you would require to achieve it, or is it more defined by the whims and fancies of the world which seemingly change every other week now?
Then, even if you did achieve it, how long would it continue to matter to you? Would you remain satisfied with it or could you become habituated to the achievement in a week, month or year and replace it another mark that would then become the one task you must complete before you die? Even if you did remain satisfied with your great achievement, would it really matter to you at the end of your life, or would you completely forget about it in the physical and mental anguish that many people seem to experience at the end of their lives?
And after you are dead, how long would that achievement be remembered before being supplanted in the public eye by something bigger?
And would it really make a difference to you at that point? Whether it remains a grand success for a thousand years or is forgotten in a day, you won't be there to know the difference anyway. It really only matters to you for the brief periods of time in which you're thinking about it right now. During times that you're distracted, tired, enjoying and appreciating something else or are simply asleep, it's hard to believe it matters at all.
If you're happy, healthy, not harming others, making a decent and honourable living, raising kids, I think you're already winning.
If the idea of having to leave a mark is making you unhappy, maybe it's better to just drop the idea.
First, what would such a mark be like for you? Is it something you could plausibly achieve with all the resources within your reach? Is it well-defined or is it nebulous? Is it likely to remain stable over the time you would require to achieve it, or is it more defined by the whims and fancies of the world which seemingly change every other week now?
Then, even if you did achieve it, how long would it continue to matter to you? Would you remain satisfied with it or could you become habituated to the achievement in a week, month or year and replace it another mark that would then become the one task you must complete before you die? Even if you did remain satisfied with your great achievement, would it really matter to you at the end of your life, or would you completely forget about it in the physical and mental anguish that many people seem to experience at the end of their lives?
And after you are dead, how long would that achievement be remembered before being supplanted in the public eye by something bigger?
And would it really make a difference to you at that point? Whether it remains a grand success for a thousand years or is forgotten in a day, you won't be there to know the difference anyway. It really only matters to you for the brief periods of time in which you're thinking about it right now. During times that you're distracted, tired, enjoying and appreciating something else or are simply asleep, it's hard to believe it matters at all.
If you're happy, healthy, not harming others, making a decent and honourable living, raising kids, I think you're already winning.
If the idea of having to leave a mark is making you unhappy, maybe it's better to just drop the idea.
it's sad to compare.
apart from that: the word "mark" comes from a root for "boundary" or "border", and really it doesn't need to be about that; we're all in this together.
apart from that: the word "mark" comes from a root for "boundary" or "border", and really it doesn't need to be about that; we're all in this together.
She's also a very talented violinist.
The key synthetic step using Ir was published after I graduated (and left Chemistry...) way to make me feel old :)
I'm very impressed by the level of chemistry demonstrated by a 17 year old. During my time as a chemistry student this level of project and synthesis probably could have been included as a chunk of a master's thesis. Did she perform all the synthesis herself? That takes a decent amount of experimental skill and more importantly what lab did she do all of this in?
Any uni ought to be delighted to get a precocious talent like this!
I'm very impressed by the level of chemistry demonstrated by a 17 year old. During my time as a chemistry student this level of project and synthesis probably could have been included as a chunk of a master's thesis. Did she perform all the synthesis herself? That takes a decent amount of experimental skill and more importantly what lab did she do all of this in?
Any uni ought to be delighted to get a precocious talent like this!
impressive for a high schooler but this just adds a protecting group onto tylenol. am i missing something?
edit: oh i see. its really blurry but the silyl modified tylenol is predicted to have good trpv1 binding computationally. afaict no in vitro or in vivo studies were done. could be cool. not sure if diethylethynylphenylsilyl group has good Lipinski properties though (i suspect not)
edit: s/aspirin/Tylenol
edit: oh i see. its really blurry but the silyl modified tylenol is predicted to have good trpv1 binding computationally. afaict no in vitro or in vivo studies were done. could be cool. not sure if diethylethynylphenylsilyl group has good Lipinski properties though (i suspect not)
edit: s/aspirin/Tylenol
It isn't aspirin - Acetaminophen, also known as N-acetyl-para-aminophenol (APAP) or paracetamol
lol yeah sorry brain too deep into synthetic chemistry bits. thanks.
[Very good comment! I'd use the opportunity to add more questions.]
How expensive are the steps? They look like advanced steps that can be done in a lab to prepare a few micrograms, but I'm not sure if they can be scaled to industrial production.
Why silicon instead of just a carbon? Is it better blocking the docking? Is it better moving the orbital energy levels? Is it as safe as the poster claim?
How expensive are the steps? They look like advanced steps that can be done in a lab to prepare a few micrograms, but I'm not sure if they can be scaled to industrial production.
Why silicon instead of just a carbon? Is it better blocking the docking? Is it better moving the orbital energy levels? Is it as safe as the poster claim?
silicon is not very successful in drugs.
https://www.science.org/content/blog-post/silicon-drug-molec...
that molecule almost certainly fails the ClogP not greater than five lipinski rule (it's too greasy)
https://www.science.org/content/blog-post/silicon-drug-molec...
that molecule almost certainly fails the ClogP not greater than five lipinski rule (it's too greasy)
[Sorry for the delay.]
IIUC from the "In the pipeline" article, drugs with silicon are too similar to their equivalent with carbon, and more difficult to make: "so why bother?"
Are they using the silicon to avoid the usual rules of substitutions in benzene cycles? Is it possible to do the same trick with carbon?
> that molecule almost certainly fails the ClogP not greater than five lipinski rule (it's too greasy)
Is it possible to fix it adding some -NH2 (or -COOH ?) group in the second aromatic cycle?
[I understand it's a nice science fair project but the article oversell it.]
IIUC from the "In the pipeline" article, drugs with silicon are too similar to their equivalent with carbon, and more difficult to make: "so why bother?"
Are they using the silicon to avoid the usual rules of substitutions in benzene cycles? Is it possible to do the same trick with carbon?
> that molecule almost certainly fails the ClogP not greater than five lipinski rule (it's too greasy)
Is it possible to fix it adding some -NH2 (or -COOH ?) group in the second aromatic cycle?
[I understand it's a nice science fair project but the article oversell it.]
I'm not an expert in pharmaceutical chemistry, but this looks like a series of relatively complex and low yield reactions. Would it be likely that this would push the price of this product beyond what is reasonable for a general use drug?
The starting point is ~free (like 2 or 4 cents retail per dose for generic in the US). Given my relatively light usage of pain drugs, I would certainly pay 10x that for reduced toxicity.
And then it isn't necessarily the case that the identified reactions are the most cost effective available.
And then it isn't necessarily the case that the identified reactions are the most cost effective available.
If you have light usage, do you need reduced toxicity?
Acetaminophen's effective dose is pretty close to the dangerous dose, but I would take light use to mean you take something maybe once a month max and only a single dose (or maybe even just one pill when the dose is two pills). At that level of use, I don't think you're at risk of anything.
Otoh, if the title is accurate and it can be more effective at pain release and less damaging to the liver, that would be great for people who experience pain frequently.
Acetaminophen's effective dose is pretty close to the dangerous dose, but I would take light use to mean you take something maybe once a month max and only a single dose (or maybe even just one pill when the dose is two pills). At that level of use, I don't think you're at risk of anything.
Otoh, if the title is accurate and it can be more effective at pain release and less damaging to the liver, that would be great for people who experience pain frequently.
If it makes it to market at a high price, it wouldn't compete directly but be targeted to those at risk of toxicity.
All my life, I've suffered from frequent (as in daily) headaches. I even have a photo of myself from my 10th birthday (or thereabouts), where you can visibly tell from how I'm holding my head that I had a headache. The nature and intensity of my headaches has changed over time.
In my 20's I discovered Excedrin (acetaminophen + caffeine) and, surprisingly, it not only worked, but worked very well. One tablet would kill most of headaches I was having at that time of my life in about 15 minutes.
Unfortunately, it stopped working for me by the time I was 30. It no longer has any noticeable effect.
Aspirin, Naproxen, Ibuprofin, and Tylenol 3 have no effect, either.
In my 20's I discovered Excedrin (acetaminophen + caffeine) and, surprisingly, it not only worked, but worked very well. One tablet would kill most of headaches I was having at that time of my life in about 15 minutes.
Unfortunately, it stopped working for me by the time I was 30. It no longer has any noticeable effect.
Aspirin, Naproxen, Ibuprofin, and Tylenol 3 have no effect, either.
Have you ruled out head/neck muscle tightness due to jaw clenching?
Have you tried muscle Botox injections? or seen a migraine specialist?
That is a tragedy. Sounds like you could use some precision medicine but it feels like that revolution is not happening fast though.
disclaimer: Not medical advice. Just an exercise in theory. See a real doctor/neurologist or migrane specialist.
I would be very suspect of a Medication Overuse Headache (MOH) due what appears to be acute/abortive use of painkiller medication as compared to a prophylactic usage of other drugs. I'll do this exercise mostly ignoring the #1 concern because presumably your doctors would be hyperaware of that.
# Pathways
0. Excedrin is combination of aspirin, acetaminophen, & caffeine.
1. Aspirin --> COX-1 (/2) inhibition --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling
2. Acetaminophen --> Central COX Inhibition, possible COX-3 inhibition (splice variant of COX-1) --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling
3.a. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Inhibition of reuptake of Anadamide (endogenous cannabinoid) --> Increased activation of CB1 receptors
3.b. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Transient Receptor Potential Vanilloid (TRPV1) agonist --> active? at periaqueductal (central) gray --> opioid receptors that send descending axons to modulate pain at the level of the dorsal horn of the spinal cord
4. Acetaminophen --> Enhancement of serotonergic descending inhibition (5-HT pathways)
5. Caffeine --> Adenosine anatagonist (nonselective A1, A2A, A2B) --> Inhibition of vasodilation --> Cerebral vasoconstriction
6. Caffeine --> Analgesic Adjuvant --> Enhances availability of aspirin and acetaminophen.
# Thoughts
1. Selective: -COX, +CB1, +TRPV1, +Opioid, -Serotenergic, -Adenosine, -Inflammation, +Vasoconstriction/-Vasodilation
2. Aspirin doesn't work in isolation.
3. Tylenol-3 (acetaminophen) doesn't work in isolation (surprising!!!).
4. Headaches probably not -COX mechanisms
5. Caffeine is likely needed for -adenosine, vasculature effect implicating cerebral vasodilation
6. Densensitization strongly implicates +CB1/+TRPV1 as well as -adenosine, +Sero, +Opioid.
# Concluding Thoughts
0. Need to address MOH, this should be a conversatio with your real doctor.
1. Then for the headache, normal first-line would probably be a TCA prophylaxis such as amitriptyline with bonus target +sero/+opioid. Assuming you've tried this.
2. The failure of your other drugs means you should probably try CGRP Inhibitors to target vascular and pain-signaling effects. Maybe even gepants (acute)
3. Botox could be a consideration in a complex CDH case.
4. Zebras: Ditan/Lasmiditan. I assumed +vasoconstriction, but could be -vasoconstriction which is why non-combination drugs failed. Target 5-HT1F and avoid vasoconstriction for symptomatic relief, but doesn't treat underlying. Probably avoid due to MOH.
# Clarifying questions for your doctor, not me
1. Is your headache pulsatile/throbbing (migrane) or dull, tight, & persistent (tension-type)?
2. Onset characterized by stress (tension-type)?
3. Is it unilateral (migrane) or bilateral (tension-type)?
# What I would do next
1. Make an appointment with a neurologist
2. Before the appointment, make a detailed headache diary (when your headaches start/end, intensity of the pain, location and quality of the pain, associated symptoms (nausea, light senstivity), any potential triggers, what you did to try to relieve the headache and if it worked)
I would be very suspect of a Medication Overuse Headache (MOH) due what appears to be acute/abortive use of painkiller medication as compared to a prophylactic usage of other drugs. I'll do this exercise mostly ignoring the #1 concern because presumably your doctors would be hyperaware of that.
# Pathways
0. Excedrin is combination of aspirin, acetaminophen, & caffeine.
1. Aspirin --> COX-1 (/2) inhibition --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling
2. Acetaminophen --> Central COX Inhibition, possible COX-3 inhibition (splice variant of COX-1) --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling
3.a. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Inhibition of reuptake of Anadamide (endogenous cannabinoid) --> Increased activation of CB1 receptors
3.b. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Transient Receptor Potential Vanilloid (TRPV1) agonist --> active? at periaqueductal (central) gray --> opioid receptors that send descending axons to modulate pain at the level of the dorsal horn of the spinal cord
4. Acetaminophen --> Enhancement of serotonergic descending inhibition (5-HT pathways)
5. Caffeine --> Adenosine anatagonist (nonselective A1, A2A, A2B) --> Inhibition of vasodilation --> Cerebral vasoconstriction
6. Caffeine --> Analgesic Adjuvant --> Enhances availability of aspirin and acetaminophen.
# Thoughts
1. Selective: -COX, +CB1, +TRPV1, +Opioid, -Serotenergic, -Adenosine, -Inflammation, +Vasoconstriction/-Vasodilation
2. Aspirin doesn't work in isolation.
3. Tylenol-3 (acetaminophen) doesn't work in isolation (surprising!!!).
4. Headaches probably not -COX mechanisms
5. Caffeine is likely needed for -adenosine, vasculature effect implicating cerebral vasodilation
6. Densensitization strongly implicates +CB1/+TRPV1 as well as -adenosine, +Sero, +Opioid.
# Concluding Thoughts
0. Need to address MOH, this should be a conversatio with your real doctor.
1. Then for the headache, normal first-line would probably be a TCA prophylaxis such as amitriptyline with bonus target +sero/+opioid. Assuming you've tried this.
2. The failure of your other drugs means you should probably try CGRP Inhibitors to target vascular and pain-signaling effects. Maybe even gepants (acute)
3. Botox could be a consideration in a complex CDH case.
4. Zebras: Ditan/Lasmiditan. I assumed +vasoconstriction, but could be -vasoconstriction which is why non-combination drugs failed. Target 5-HT1F and avoid vasoconstriction for symptomatic relief, but doesn't treat underlying. Probably avoid due to MOH.
# Clarifying questions for your doctor, not me
1. Is your headache pulsatile/throbbing (migrane) or dull, tight, & persistent (tension-type)?
2. Onset characterized by stress (tension-type)?
3. Is it unilateral (migrane) or bilateral (tension-type)?
# What I would do next
1. Make an appointment with a neurologist
2. Before the appointment, make a detailed headache diary (when your headaches start/end, intensity of the pain, location and quality of the pain, associated symptoms (nausea, light senstivity), any potential triggers, what you did to try to relieve the headache and if it worked)
Can acetaminophen be packaged with n-acetyl cysteine to render it not rate limited by same?
The problem is that N-acetylcysteine tastes and smells awful (like farts/rotten eggs) and often causes nausea and vomiting as a side effect.
The vast majority of people use acetaminophen in a safe way, and acetaminophen doesn't really have many side effects by itself, so you'd make life more unpleasant for a large number of people in order to prevent a tiny number of acute poisonings.
Probably if this were implemented, most acetaminophen users would switch to e.g. ibuprofen which is less acutely toxic in overdose but has much more chronic toxicity (to the stomach and the kidneys) when used over a long period of time, even at a normal dose. I'd wager this change might even be a net negative on the whole.
The vast majority of people use acetaminophen in a safe way, and acetaminophen doesn't really have many side effects by itself, so you'd make life more unpleasant for a large number of people in order to prevent a tiny number of acute poisonings.
Probably if this were implemented, most acetaminophen users would switch to e.g. ibuprofen which is less acutely toxic in overdose but has much more chronic toxicity (to the stomach and the kidneys) when used over a long period of time, even at a normal dose. I'd wager this change might even be a net negative on the whole.
Experiences may vary; I’ve tasted and smelled NAC.
The smell is reminescent of a high-potency cannabis strain. (Sulfur-containing molecules.)
The taste is very acidic and a bit astringent.
Generally the smell and taste of something isn’t a concern with medication. I don’t think acetaminophen tastes great.
I’ve never encountered or seen the digestive issues that are often mentioned. I’ve seen other side effects which were noticeable – mast cell and histamine related I believe, kind of weird ones, like psoriasis kind of drying out a bit and the skin on the lips “refreshing” itself. (Really!) Subtle side effects and hard to put into words without making them seem bigger and weirder than they are, but NAC can nonetheless be a sort of histamine and mast cell “flusher”, so to speak and as it seems. Beneficial in the long run imo ime, but tricky to package universally.
Still, NAC is also tragically unknown and unused! There’s tons of fascinating literature on it. They fried rats’ brains with methamphetamine and fixed them with NAC; Brutal study, intriguing results on very significant mechanisms.
The smell is reminescent of a high-potency cannabis strain. (Sulfur-containing molecules.)
The taste is very acidic and a bit astringent.
Generally the smell and taste of something isn’t a concern with medication. I don’t think acetaminophen tastes great.
I’ve never encountered or seen the digestive issues that are often mentioned. I’ve seen other side effects which were noticeable – mast cell and histamine related I believe, kind of weird ones, like psoriasis kind of drying out a bit and the skin on the lips “refreshing” itself. (Really!) Subtle side effects and hard to put into words without making them seem bigger and weirder than they are, but NAC can nonetheless be a sort of histamine and mast cell “flusher”, so to speak and as it seems. Beneficial in the long run imo ime, but tricky to package universally.
Still, NAC is also tragically unknown and unused! There’s tons of fascinating literature on it. They fried rats’ brains with methamphetamine and fixed them with NAC; Brutal study, intriguing results on very significant mechanisms.
I take NAC to help with hangovers, I used to get smashing headaches and people would recommend random Korean and japanese 'hangover supplements', I was obviously very skeptical and googled every ingredient to check it is safe. The ones that worked had NAC or gluthanione. Looked into it and bought some and always take it when I drink or have panadol. Have not noticed any other subjective effects
Nausea or vomitting is rare, I imagine if it were common those hangover cure sellers would go out of business
Nausea or vomitting is rare, I imagine if it were common those hangover cure sellers would go out of business
Interesting!, thanks! NAC is all over the place; I didn’t know about this application.
And yeah I was 100% skeptical too!
Now I’m more sceptical of the kinda “nothing is known, nothing is knowable” angle, you know? There is so much knowledge, actionable, often unread, often unused.
(Have to mention it, if useful: Na—R-ALA (alpha lipoic acid) and ambroxol are kind of in the same vein. Ambroxol is strangely a sort of bromine counterpart to NAC and its sulfur atom. Sold as a mucolytic but is… alllll over the place. Funny how mucus, mucous membranes, the nervous system, and oxidation/redox stuff is all so adjacent it seems.
I have no idea why but after a severe period of stress, I happened to take Na-R-ALA as sometimes do and 60mg of ambroxol as mucolytic cough syrup. For a cough. And… the feeling was like in the movies where they stab someone with a giant syringe to revive them. Trainspotting or Pulp Fiction or whatever. I felt like I gasp-crawled out of a pit inside myself. It makes no sense. It was… a very distinct experience. And it didn’t seem like an airway clearance thing, more like my nervous system was refreshed.
So I hit the books. And it turns out ambroxol crosses the blood-brain barrier and is an antioxidant, and affects ion balance in neurons, and there are studies indicating it helps with… Parkinson’s and fibromyalgia (!!!). And those papers are pretty interesting and appear to be constructed on solid molecular biological premises.
idk)
And yeah I was 100% skeptical too!
Now I’m more sceptical of the kinda “nothing is known, nothing is knowable” angle, you know? There is so much knowledge, actionable, often unread, often unused.
(Have to mention it, if useful: Na—R-ALA (alpha lipoic acid) and ambroxol are kind of in the same vein. Ambroxol is strangely a sort of bromine counterpart to NAC and its sulfur atom. Sold as a mucolytic but is… alllll over the place. Funny how mucus, mucous membranes, the nervous system, and oxidation/redox stuff is all so adjacent it seems.
I have no idea why but after a severe period of stress, I happened to take Na-R-ALA as sometimes do and 60mg of ambroxol as mucolytic cough syrup. For a cough. And… the feeling was like in the movies where they stab someone with a giant syringe to revive them. Trainspotting or Pulp Fiction or whatever. I felt like I gasp-crawled out of a pit inside myself. It makes no sense. It was… a very distinct experience. And it didn’t seem like an airway clearance thing, more like my nervous system was refreshed.
So I hit the books. And it turns out ambroxol crosses the blood-brain barrier and is an antioxidant, and affects ion balance in neurons, and there are studies indicating it helps with… Parkinson’s and fibromyalgia (!!!). And those papers are pretty interesting and appear to be constructed on solid molecular biological premises.
idk)
That's interesting I took r-ALA before, cannot recall dosage but felt nothing of that sort or subjective/psychoactive at all. Several people I know report acute changes too when taking lion's mane but I don't
Interesting, right?
As a detail, I clearly experience the better bioavailability of Na-R-ALA. Often marketed as “stabilized”. As well as what I believe is the increased bioavailability of Na-R-ALA dissolved in water.
The main point I wanted to make is that it occurred to me when reading your comment that I know myself to be somewhat “oxidatively burdened”, if that’s a term? I have mild psoriasis, which is known to use oxidative and redox capacity in the immune system’s activation in the rash. (afaik immune cells “fire bullets” of oxidization at perceived intruders.) There are other stressors in my life which are also inherently oxidising in the molecular biology of it. I’d bet a nice bottle of Oban that that is a factor in the sense of relief.
As a detail, I clearly experience the better bioavailability of Na-R-ALA. Often marketed as “stabilized”. As well as what I believe is the increased bioavailability of Na-R-ALA dissolved in water.
The main point I wanted to make is that it occurred to me when reading your comment that I know myself to be somewhat “oxidatively burdened”, if that’s a term? I have mild psoriasis, which is known to use oxidative and redox capacity in the immune system’s activation in the rash. (afaik immune cells “fire bullets” of oxidization at perceived intruders.) There are other stressors in my life which are also inherently oxidising in the molecular biology of it. I’d bet a nice bottle of Oban that that is a factor in the sense of relief.
> I was obviously very skeptical and googled every ingredient to check it is safe.
Did you check if drinking alcohol was safe? ;)
Did you check if drinking alcohol was safe? ;)
No because I already know the answer to that!
Always wondered that.
Maybe too many people would take even more?
Maybe too many people would take even more?
Reminds me of this drug company I was pitched a while ago:
https://en.wikipedia.org/wiki/Antibe_Therapeutics
https://en.wikipedia.org/wiki/Antibe_Therapeutics
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This is nothing. My kid discovered dark matter (in middle school).
so is this already patented by Regeneron?
regeneron is the sponsor of STS. used to be well known as the Westinghouse STS, then intel took it over in the aughts
They're testing it now against all of their genetic targets they bought from 23andMe
They would need to show efficacy to patent it. It seems like this is all computational.
Only for a utility patent, not for a composition of matter patent.
no she did the synthesis and the yields are averaged? over >5 replicates <== just doing that is pretty (spiritually?) impressive, most phd chemists wouldn't do that kind of reproduction of results.
acetaminophen is paracetamol
I didn't understand why this post had so many votes
I didn't understand why this post had so many votes
How about don’t fucking take it because it’s toxic?