6 ms·

Really lovely article. In paramedicine we usually treat 10g of acetaminophen in a 24-hour window as a potentially fatal overdose. That's also why the law in Aus

by pugio 5mo ago

Really lovely article. In paramedicine we usually treat 10g of acetaminophen in a 24-hour window as a potentially fatal overdose. That's also why the law in Australia was changed to require acetaminophen to come in blister packs (harder to get each pill out) of no more than 16. At 500 mg, that only gets you up to 8 g if you eat the whole thing, which is still hopefully non-fatal. I always thought a simple over-the-counter supplement (NAC) being the cure for an overdose was so cool. It's a pretty cool substance in a lot of ways, and this is a great spur to myself to research it more thoroughly.

tokyobreakfast 5mo ago
You can still die if you take your idiot-proof Aussie blister packs with alcohol. So it's more an inefficient use of cabinet space. You can overdose on water too, they haven't banned 5-gallon jugs (yet).
- adithyareddy 5mo ago
  Yes, and you can still die in a car crash if you're wearing your seatbelt, and wearing a helmet on your motorcycle won't save you from a head-on with a truck, and you can still drown in a pool with a lifeguard, and you can still die in a burning building with smoke detectors. Harm reduction is about shifting probability distributions, not guaranteeing outcomes. Kids can still get into pill bottles with childproof medication caps, but accidental ingestion of aspirin by children reduced by 40-55% after they were mandated. [0] [0]: https://pubmed.ncbi.nlm.nih.gov/440889/ https://pubmed.ncbi.nlm.nih.gov/440889/
- epcoa 5mo ago
  No. Ethanol and tylenol compete for CYP2E1 that produces toxic NAPQI, so no, acute alcohol intoxication has a protective effect at least where it comes to tylenol toxicity.
  - Flashtoo 5mo ago
    This is correct.
  - robocat 5mo ago
    No. Alcohol and Acetominophen/paracetamol should not be mixed. When alcohol enters the picture, it increases the activity of CYP2E1, so the body produces more of the NAPQI toxin. Alcohol also decreases glutathione production, the body’s natural defense mechanism, meaning NAPQI is more likely to build up in the liver in dangerous concentrations. https://www.medicalnewstoday.com/articles/322813 https://www.medicalnewstoday.com/articles/322813 Sorry, crappy link. If you don't like it, it is easy to search for a better one.
    - Flashtoo 5mo ago
      There is a danger in chronic abuse resulting in upregulation. Mixing the two at once is no problem for the liver, which is also why patient information leaflets for paracetamol do not contain a warning to avoid alcohol, only about chronic alcohol abuse. Your crappy source is vague in what consumption pattern constitutes a risk and actually cites a better source that supports the idea that acute alcohol consumption reduces paracetamol toxicity. https://www.biorxiv.org/content/10.1101/2020.07.07.191916v1.full https://www.biorxiv.org/content/10.1101/2020.07.07.191916v1.... That's a mathematical model, but this relationship between the two is what I was taught in medical school and it is still supported by the science. There's plenty of other sources, I just picked that one because your article cites it. Just search for "paracetamol ethanol" on Google Scholar.
- perching_aix 5mo ago
  s/idiot-proof/idiot-resistant/g Also applies to most similar phrases ending in -proof. Should be eye-opening.
Nursie 5mo ago
When was this changed? I arrived in Aus in 2021 and was amazed to be able to buy a pack of 40+, coming from the UK where the limit had been in place for some years.
- pugio 5mo ago
  Jan 2025: https://www.psa.org.au/changes-to-paracetamol-scheduling-will-reduce-risk-of-harm-to-children-and-adolescents/ https://www.psa.org.au/changes-to-paracetamol-scheduling-wil... It's the usual public health balancing act of help vs harm.
- brainwad 5mo ago
  You can still buy 100 packs, they are just behind the counter at chemists. TBH it's a rather stupid restriction - do they think people only ever own 1 packet of paracetamol at a time? In my household we have at least half a dozen, including a 100-pack from Oz and a 500-pack from America.
  - Nursie 5mo ago
    Oh right - that's probably what we did, buy a big pack from behind the counter. I don't think you can even do that in the UK. Yeah we usually have a few packs hanging around, and I get the 'it seems stupid' thing, but sometimes just adding a tiny bit of friction when someone's trying to kill themselves might save a life. I dunno, I hope that's shown in the evidence anyway. Otherwise it's just pointless like the whole pseudoephedrine song and dance, which has inconvenienced anyone looking for a decongestant while doing sweet FA to the availability of meth.
    - zimpenfish 5mo ago
      > I hope that's shown in the evidence anyway tl;dr: Yes Paraphrasing from [0], after September 1998 when the restriction was introduced, "The annual number of deaths from paracetamol poisoning decreased by 21% [...] the number from salicylates decreased by 48% [...] Liver transplant rates after paracetamol poisoning decreased by 66% [...] The rate of non-fatal self poisoning with paracetamol in any form decreased by 11%" See also [1]: "in the 11 years following the legislation there were an estimated 765 fewer suicide and open verdict deaths from paracetamol poisoning, which represented a reduction of 43% [...] This reduction was largely unaltered after controlling for a downward trend in deaths involving other methods of poisoning and also suicides by all methods." [0] https://pmc.ncbi.nlm.nih.gov/articles/PMC31616/ https://pmc.ncbi.nlm.nih.gov/articles/PMC31616/ [1] https://www.psych.ox.ac.uk/research/research-groups/csr/research-topics/pack-sizes https://www.psych.ox.ac.uk/research/research-groups/csr/rese...
throwaway27448 5mo ago
What does ingesting 10g of acetaminophen even look like? I've got to imagine the fatal dose is far, far, far lower with chronic usage. Finding out that people are ingesting grams is profoundly disturbing.
- petesergeant 5mo ago
  > What does ingesting 10g of acetaminophen even look like? 20 not-especially-large tablets
  - vasco 5mo ago
    Or 10 slightly larger ones edit: https://www.24pharma.nl/paracetamol-eg-1000mg-120-tabletten https://www.24pharma.nl/paracetamol-eg-1000mg-120-tabletten
    - petesergeant 5mo ago
      I’ve pretty much only ever seen them sold at 500mg; are you regularly seeing them where you are sold in 1g form?
      - nbernard 5mo ago
        They are common in France, but not in such packages: There are restrictions that prevent you from buying more than than 8g/day (theoretically at least, I don't believe they are strictly applied in practice).
      - Dries007 5mo ago
        The linked size is also quite common in Belgium.
      - oblio 5mo ago
        In Europe for sure they're also sold in 1g dosing. I think the packages don't contain lots of pills, though. Definitely not US style buckets of pills.
      - 5mo ago
rao-v 5mo ago
Could somebody package Tylenol with a sufficient amount of NAC to de-risk it? I suspect such a formulation would not require trials?
- djsavvy 5mo ago
  See superscript 6 on the article. Apparently NAC might has side effects of its own.
  - keane 5mo ago
    One of the side effects in a study in mice was inducing lung cancer: https://doi.org/10.1172/jci.insight.127647 https://doi.org/10.1172/jci.insight.127647
    - rao-v 5mo ago
      Ah
- 986aignan 5mo ago
  Certain esters have been found to be much safer (in mice, at least): > The glutathione hepatic values in mice obtained by intraperitoneal injection of the ester are superimposable on controls and the oral LD50 was found to be greater than 2000 mg kg^-1 and the intraperitoneal LD50 was 1900 mg kg^-1 ... That's for pyroglutamic and glutamic acid esters of paracetamol: https://pubmed.ncbi.nlm.nih.gov/8799871/ https://pubmed.ncbi.nlm.nih.gov/8799871/ and more general analogs apparently can also be designed to not produce NAPQI: > Thus, in 2020, N-sulpharyl-APAP prodrugs 39–40 (Fig. 11) were developed. [...] They are not hepatotoxic because they do not generate toxic metabolite NAPQI, even in concentrations equal to a toxic dose of APAP (600 mg kg^−1 in mice). https://pubs.rsc.org/zh-tw/content/articlepdf/2024/ra/d4ra00365a https://pubs.rsc.org/zh-tw/content/articlepdf/2024/ra/d4ra00... p. 9702. These would probably require trials, though.
Natsu 5mo ago
I've heard it suggested that acetaminophen just come with a small dose of NAC alongside it to make it safer. I guess this would require a lot of regulatory work to approve, but given that 500 people a year OD, it seems like a thing we should at least consider. Meanwhile, it's funny that it seems like acetaminophen should safer in more scenarios, but the other has a lot of overdoses with typical use, I guess that's why there's a gap between the two, because ODs are apparently a lot more common or at least more legible than problems caused by the other drug.
eru 5mo ago
Here in Singapore NAC is sold to make muckus more liquid to alleviate coughs. Apparently for some people it also helps with lessening tolerance for their ADHD meds, but I'm not so sure about that.
- user_7832 5mo ago
  > Apparently for some people it also helps with lessening tolerance for their ADHD meds, but I'm not so sure about that. I'd believe it. I first heard of NAC on the nootropic subreddit in a past lifetime. The benefits vary, but generally it's a safe thing with a low chance of making anything worse, but a possibility to improve things. Many neurodivergent folk have written about how they benefit. I'd give more info on the exact benefits they found (iirc OCD and rumination loops could be broken more easily), but unfortunately my memory is failing me.
  - jcynix 5mo ago
    You'll find a detailed description oft potential effects and uses here: https://en.wikipedia.org/wiki/Acetylcysteine https://en.wikipedia.org/wiki/Acetylcysteine (aka NAC)
- CalRobert 5mo ago
  How is nac (acetylcysteine) delivered there? I can buy dissolvable tablets here in Europe but from what I see that’s less helpful for mucous, things like mucomyst require inhalation, which isn’t in otc products I know of.
  - jack_pp 5mo ago
    Same where I'm from, it's in pill / capsule form
  - rdevilla 5mo ago
    In the Philippines it's available as an effervescent tablet to be dissolved in water. They still tend to work better than the western remedies (guaifenesin etc) even in this form IME. Usually here in Canada it's available in capsule form which I find less effective.
triage8004 5mo ago
NAC is so amazing for us in terribly polluted areas. Also great before drinking
- garyclarke27 5mo ago
  Glycine + NAC even better, both precursors for Glutathione, Glycine also great for sleeping.
- harmonics 5mo ago
  I am blessed with living in one of the most polluted areas in the world (PM2.5 going into thousands of µg/m³ in winter; summers are not much better due to dense chemical smog). Can you say more about how you're using it to combat that? Thanks!
dgan 5mo ago
I randomly bought NAC just to try it. I dont know about the chemical interactions, but going out with collegues at that time taught me that it's basically impossible to get drunk. Usually a pint of beer is enough to make le feel at least a little dizzy, but when taking NAC, it was all like drinking water
- elric 5mo ago
  When I go out drinking with my pharmacist buddy, we take NAC before going out. He swears it makes hangovers less likely. I can't say I've noticed that particular effect, but I do seem to sleep a bit better on those nights.
- jcynix 5mo ago
  NAC taken before consuming alcohol has a positive effect apparently, but taken afterwards it's detrimental as mentioned here: https://en.wikipedia.org/wiki/Acetylcysteine https://en.wikipedia.org/wiki/Acetylcysteine
  - ButlerianJihad 5mo ago
    Vaccine Ordering https://xkcd.com/2422/ https://xkcd.com/2422/
    - dgan 5mo ago
      Took me a while, because i pronounce "Pfizer" as "pfee-tseh-r" in my head
      - cubefox 5mo ago
        That's the original pronunciation
        cubefox 5mo ago
        Not sure why this is voted down, it's true.
ncruces 5mo ago
Similar rules in Europe, or at least, Portugal.

by pugio 5mo ago

tokyobreakfast 5mo ago

You can still die if you take your idiot-proof Aussie blister packs with alcohol. So it's more an inefficient use of cabinet space. You can overdose on water too, they haven't banned 5-gallon jugs (yet).

adithyareddy 5mo ago
Yes, and you can still die in a car crash if you're wearing your seatbelt, and wearing a helmet on your motorcycle won't save you from a head-on with a truck, and you can still drown in a pool with a lifeguard, and you can still die in a burning building with smoke detectors. Harm reduction is about shifting probability distributions, not guaranteeing outcomes. Kids can still get into pill bottles with childproof medication caps, but accidental ingestion of aspirin by children reduced by 40-55% after they were mandated. [0] [0]: https://pubmed.ncbi.nlm.nih.gov/440889/ https://pubmed.ncbi.nlm.nih.gov/440889/
epcoa 5mo ago
No. Ethanol and tylenol compete for CYP2E1 that produces toxic NAPQI, so no, acute alcohol intoxication has a protective effect at least where it comes to tylenol toxicity.
- Flashtoo 5mo ago
  This is correct.
- robocat 5mo ago
  No. Alcohol and Acetominophen/paracetamol should not be mixed. When alcohol enters the picture, it increases the activity of CYP2E1, so the body produces more of the NAPQI toxin. Alcohol also decreases glutathione production, the body’s natural defense mechanism, meaning NAPQI is more likely to build up in the liver in dangerous concentrations. https://www.medicalnewstoday.com/articles/322813 https://www.medicalnewstoday.com/articles/322813 Sorry, crappy link. If you don't like it, it is easy to search for a better one.
  - Flashtoo 5mo ago
    There is a danger in chronic abuse resulting in upregulation. Mixing the two at once is no problem for the liver, which is also why patient information leaflets for paracetamol do not contain a warning to avoid alcohol, only about chronic alcohol abuse. Your crappy source is vague in what consumption pattern constitutes a risk and actually cites a better source that supports the idea that acute alcohol consumption reduces paracetamol toxicity. https://www.biorxiv.org/content/10.1101/2020.07.07.191916v1.full https://www.biorxiv.org/content/10.1101/2020.07.07.191916v1.... That's a mathematical model, but this relationship between the two is what I was taught in medical school and it is still supported by the science. There's plenty of other sources, I just picked that one because your article cites it. Just search for "paracetamol ethanol" on Google Scholar.
perching_aix 5mo ago
s/idiot-proof/idiot-resistant/g Also applies to most similar phrases ending in -proof. Should be eye-opening.

Nursie 5mo ago

When was this changed? I arrived in Aus in 2021 and was amazed to be able to buy a pack of 40+, coming from the UK where the limit had been in place for some years.

pugio 5mo ago
Jan 2025: https://www.psa.org.au/changes-to-paracetamol-scheduling-will-reduce-risk-of-harm-to-children-and-adolescents/ https://www.psa.org.au/changes-to-paracetamol-scheduling-wil... It's the usual public health balancing act of help vs harm.
brainwad 5mo ago
You can still buy 100 packs, they are just behind the counter at chemists. TBH it's a rather stupid restriction - do they think people only ever own 1 packet of paracetamol at a time? In my household we have at least half a dozen, including a 100-pack from Oz and a 500-pack from America.
- Nursie 5mo ago
  Oh right - that's probably what we did, buy a big pack from behind the counter. I don't think you can even do that in the UK. Yeah we usually have a few packs hanging around, and I get the 'it seems stupid' thing, but sometimes just adding a tiny bit of friction when someone's trying to kill themselves might save a life. I dunno, I hope that's shown in the evidence anyway. Otherwise it's just pointless like the whole pseudoephedrine song and dance, which has inconvenienced anyone looking for a decongestant while doing sweet FA to the availability of meth.
  - zimpenfish 5mo ago
    > I hope that's shown in the evidence anyway tl;dr: Yes Paraphrasing from [0], after September 1998 when the restriction was introduced, "The annual number of deaths from paracetamol poisoning decreased by 21% [...] the number from salicylates decreased by 48% [...] Liver transplant rates after paracetamol poisoning decreased by 66% [...] The rate of non-fatal self poisoning with paracetamol in any form decreased by 11%" See also [1]: "in the 11 years following the legislation there were an estimated 765 fewer suicide and open verdict deaths from paracetamol poisoning, which represented a reduction of 43% [...] This reduction was largely unaltered after controlling for a downward trend in deaths involving other methods of poisoning and also suicides by all methods." [0] https://pmc.ncbi.nlm.nih.gov/articles/PMC31616/ https://pmc.ncbi.nlm.nih.gov/articles/PMC31616/ [1] https://www.psych.ox.ac.uk/research/research-groups/csr/research-topics/pack-sizes https://www.psych.ox.ac.uk/research/research-groups/csr/rese...

throwaway27448 5mo ago

What does ingesting 10g of acetaminophen even look like? I've got to imagine the fatal dose is far, far, far lower with chronic usage. Finding out that people are ingesting grams is profoundly disturbing.

petesergeant 5mo ago
> What does ingesting 10g of acetaminophen even look like? 20 not-especially-large tablets
- vasco 5mo ago
  Or 10 slightly larger ones edit: https://www.24pharma.nl/paracetamol-eg-1000mg-120-tabletten https://www.24pharma.nl/paracetamol-eg-1000mg-120-tabletten
  - petesergeant 5mo ago
    I’ve pretty much only ever seen them sold at 500mg; are you regularly seeing them where you are sold in 1g form?
    - nbernard 5mo ago
      They are common in France, but not in such packages: There are restrictions that prevent you from buying more than than 8g/day (theoretically at least, I don't believe they are strictly applied in practice).
    - Dries007 5mo ago
      The linked size is also quite common in Belgium.
    - oblio 5mo ago
      In Europe for sure they're also sold in 1g dosing. I think the packages don't contain lots of pills, though. Definitely not US style buckets of pills.
    - 5mo ago

rao-v 5mo ago

Could somebody package Tylenol with a sufficient amount of NAC to de-risk it? I suspect such a formulation would not require trials?

djsavvy 5mo ago
See superscript 6 on the article. Apparently NAC might has side effects of its own.
- keane 5mo ago
  One of the side effects in a study in mice was inducing lung cancer: https://doi.org/10.1172/jci.insight.127647 https://doi.org/10.1172/jci.insight.127647
  - rao-v 5mo ago
    Ah
986aignan 5mo ago
Certain esters have been found to be much safer (in mice, at least): > The glutathione hepatic values in mice obtained by intraperitoneal injection of the ester are superimposable on controls and the oral LD50 was found to be greater than 2000 mg kg^-1 and the intraperitoneal LD50 was 1900 mg kg^-1 ... That's for pyroglutamic and glutamic acid esters of paracetamol: https://pubmed.ncbi.nlm.nih.gov/8799871/ https://pubmed.ncbi.nlm.nih.gov/8799871/ and more general analogs apparently can also be designed to not produce NAPQI: > Thus, in 2020, N-sulpharyl-APAP prodrugs 39–40 (Fig. 11) were developed. [...] They are not hepatotoxic because they do not generate toxic metabolite NAPQI, even in concentrations equal to a toxic dose of APAP (600 mg kg^−1 in mice). https://pubs.rsc.org/zh-tw/content/articlepdf/2024/ra/d4ra00365a https://pubs.rsc.org/zh-tw/content/articlepdf/2024/ra/d4ra00... p. 9702. These would probably require trials, though.

Natsu 5mo ago

I've heard it suggested that acetaminophen just come with a small dose of NAC alongside it to make it safer. I guess this would require a lot of regulatory work to approve, but given that 500 people a year OD, it seems like a thing we should at least consider. Meanwhile, it's funny that it seems like acetaminophen should safer in more scenarios, but the other has a lot of overdoses with typical use, I guess that's why there's a gap between the two, because ODs are apparently a lot more common or at least more legible than problems caused by the other drug.

eru 5mo ago

Here in Singapore NAC is sold to make muckus more liquid to alleviate coughs. Apparently for some people it also helps with lessening tolerance for their ADHD meds, but I'm not so sure about that.

user_7832 5mo ago
> Apparently for some people it also helps with lessening tolerance for their ADHD meds, but I'm not so sure about that. I'd believe it. I first heard of NAC on the nootropic subreddit in a past lifetime. The benefits vary, but generally it's a safe thing with a low chance of making anything worse, but a possibility to improve things. Many neurodivergent folk have written about how they benefit. I'd give more info on the exact benefits they found (iirc OCD and rumination loops could be broken more easily), but unfortunately my memory is failing me.
- jcynix 5mo ago
  You'll find a detailed description oft potential effects and uses here: https://en.wikipedia.org/wiki/Acetylcysteine https://en.wikipedia.org/wiki/Acetylcysteine (aka NAC)
CalRobert 5mo ago
How is nac (acetylcysteine) delivered there? I can buy dissolvable tablets here in Europe but from what I see that’s less helpful for mucous, things like mucomyst require inhalation, which isn’t in otc products I know of.
- jack_pp 5mo ago
  Same where I'm from, it's in pill / capsule form
- rdevilla 5mo ago
  In the Philippines it's available as an effervescent tablet to be dissolved in water. They still tend to work better than the western remedies (guaifenesin etc) even in this form IME. Usually here in Canada it's available in capsule form which I find less effective.

triage8004 5mo ago

NAC is so amazing for us in terribly polluted areas. Also great before drinking

garyclarke27 5mo ago
Glycine + NAC even better, both precursors for Glutathione, Glycine also great for sleeping.
harmonics 5mo ago
I am blessed with living in one of the most polluted areas in the world (PM2.5 going into thousands of µg/m³ in winter; summers are not much better due to dense chemical smog). Can you say more about how you're using it to combat that? Thanks!

dgan 5mo ago

I randomly bought NAC just to try it. I dont know about the chemical interactions, but going out with collegues at that time taught me that it's basically impossible to get drunk. Usually a pint of beer is enough to make le feel at least a little dizzy, but when taking NAC, it was all like drinking water

elric 5mo ago
When I go out drinking with my pharmacist buddy, we take NAC before going out. He swears it makes hangovers less likely. I can't say I've noticed that particular effect, but I do seem to sleep a bit better on those nights.
jcynix 5mo ago
NAC taken before consuming alcohol has a positive effect apparently, but taken afterwards it's detrimental as mentioned here: https://en.wikipedia.org/wiki/Acetylcysteine https://en.wikipedia.org/wiki/Acetylcysteine
- ButlerianJihad 5mo ago
  Vaccine Ordering https://xkcd.com/2422/ https://xkcd.com/2422/
  - dgan 5mo ago
    Took me a while, because i pronounce "Pfizer" as "pfee-tseh-r" in my head
    - cubefox 5mo ago
      That's the original pronunciation
      - cubefox 5mo ago
        Not sure why this is voted down, it's true.

ncruces 5mo ago

Similar rules in Europe, or at least, Portugal.