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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.
"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.
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.
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.
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.
But how many cases of poisoning occur each year?
> 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.
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.
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.
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
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.
Reversible computing, materials science, genetic research… it’s insane that these kids are doing this level of work in high school.
> 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.
I thought morphine didn't cause health damage to the human body apart from addiction and withdrawal symptoms.
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.
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.
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.
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!
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
It isn't aspirin - Acetaminophen, also known as N-acetyl-para-aminophenol (APAP) or paracetamol
[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?
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.
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.
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)
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.
Always wondered that.
Maybe too many people would take even more?
Reminds me of this drug company I was pitched a while ago:
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.
acetaminophen is paracetamol
I didn't understand why this post had so many votes
How about don’t fucking take it because it’s toxic?