Scientists have just upended decades of assumptions about how Tylenol works.
A new study reveals that the common painkiller doesn’t relieve pain by increasing natural feel-good chemicals, as once believed, but by lowering one of them. This surprising reversal could open the door to a new generation of safer, more effective pain medications and reshape how we understand everyday drugs like Tylenol.
Breakthrough Discovery in Tylenol Research
A new discovery from scientists at Indiana University is shedding light on one of the most widely used over-the-counter drugs: Tylenol. This breakthrough could help researchers design better, safer pain medications in the future.
The study, led by Michaela Dvorakova and Alex Straiker at IU’s Gill Institute for Neuroscience, was recently published in Cell Reports Medicine. Their findings reveal a previously unknown way that acetaminophen, the active ingredient in Tylenol, targets pain in the body.
The Role of Endocannabinoids in Pain Relief
The team discovered that acetaminophen blocks an enzyme responsible for producing 2-arachidonoyl glycerol, or 2-AG. This compound is part of a group of naturally occurring brain chemicals called endocannabinoids, which activate receptors in the body known to influence pain, mood, and even the effects of cannabis.
Although Tylenol is the most commonly used medication for pain and fever in the United States, its exact mechanism has remained uncertain for decades.
“There are hypotheses, but we still don’t know precisely how it works,” Dvorakova said. “Up until now we thought that elevated endocannabinoids in our body meant less pain, but our study shows that in the case of 2-AG, it might be the opposite. Actually, reduced levels of 2-AG lead to decreased pain.”
A Safer Future for Pain Medications
In high doses, acetaminophen can be toxic to the liver. Acetaminophen toxicity causes around 500 deaths per year in the U.S. and is the second leading cause of liver transplantation around the world. Due to its wide availability and its combination in other products, more than 60 million Americans consume acetaminophen weekly, making it crucial to understand how it targets pain receptors.
“If you don’t know what the target is, you can’t design an alternative,” Straiker said. “Our research suggests that this enzyme might be the target, in which case you can start developing drugs that target that specific enzyme but without that toxicity.”
Challenging Scientific Dogma
Straiker said there was skepticism in the research community about a new mechanism of action for acetaminophen. When 50 years of research showed that activating CB1 receptors produced pain relief in the body, scientists settled on that concept.
“It can be hard to break through that dogma,” Straiker said.
What’s Next: Beyond Tylenol
Going forward, the research team is looking into evaluating other common pain relievers, like ibuprofen and aspirin, to determine whether they have similar mechanisms of action.
Reference: “Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: Implications for nociception” by Michaela Dvorakova, Taryn Bosquez-Berger, Jenna Billingsley, Natalia Murataeva, Taylor Woodward, Emma Leishman, Anaëlle Zimmowitch, Anne Gibson, Jim Wager-Miller, Ruyi Cai, Shangxuan Cai, Tim Ware, Ku-Lung Hsu, Yulong Li, Heather Bradshaw, Ken Mackie and Alex Straiker, 16 May 2025, Cell Reports Medicine.
DOI: 10.1016/j.xcrm.2025.102139
The research team included a wide range of experts from across the globe. Alongside lead scientists Michaela Dvorakova and Alex Straiker, contributors included Ken Mackie from IU’s Gill Institute. Additional collaborators from Indiana University were Taryn Bosquez-Berger, Jenna Billingsley, Natalia Murataeva, Taylor Woodward, Emma Leishman, Anaëlle Zimmowitch, Anne Gibson, Jim Wager-Miller, and Heather Bradshaw. The study also involved researchers from Peking University’s School of Life Sciences, including Ruyi Cai, Shangxuan Cai, and Yulong Li, as well as Tim Ware from Scripps Research Institute and Ku-Lung Hsu from the University of Texas at Austin.
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15 Comments
Tylenol is very bad for the liver, pancreas, and kidneys. Tylenol imo is dangerous to humans.
I totally agree. My husband is living proof having been in palliative care he doesn’t have kidney pancreas or any liver damage from opiates without Tylenol. He’s had to take pain meds for over 20 years and had he taken it with Tylenol he’d be dead by now.
FDA right on top of things.
Tylenol is used as a filler by all drug manufacturers in the US for codeine, oxycodone, etc.
We can’t avoid it.
Strange that the article names Tylenol which is a brand name in the title instead of acetaminophen which is the name of the active drug.
I’ve been using Tylenol for 50 years and have not had any adverse effects. My doctor tells me that it has a lot to do with diet, weight, other medications AND alcohol intake.
I really think it all comes down to common sense. Life is full of those thoughts.
Have a wonderful Memorial Day. Enjoy your freedom.
Kudos to Johnson & Johnson who promote things like Tylenol and Sucralose as “Safe”!
People die from peanuts too…
One of the interesting things about humans is the wide range of responses to medications and even placebos. Toxins are rated with what is called the LD50, or lethal dose for 50% of those who receive the particular toxin. The test subjects are usually small rodents such as mice and rats. I would expect that humans would demonstrate a wider range of tolerance.
That is consistent with the general understanding of what Tylenol does – it doesn’t reduce whatever is causing the pain, it reduces the ‘felt sensation’ of pain.
“The team discovered that acetaminophen blocks an enzyme responsible for producing 2-arachidonoyl glycerol, or 2-AG. This compound is part of a group of naturally occurring brain chemicals called endocannabinoids, which activate receptors in the body known to influence pain, mood, and even the effects of cannabis.”
Well, the first three words of the headline are accurate: “Tylenol Doesn’t Work”.
Doesn’t matter why or how it doesn’t, just that it doesn’t. Tylenol for pain relief is like trying to get high off oregano.
I have to agree with the findings regarding acetaminophen. I’ve tried for years to make doctors believe and understand that this drug does NOT work for me to relieve pain. It never has yet that’s the only thing they want me to take. It’s no different than them not believing me about menstrual problems and conceive for reproduction. One doctor finally listened when I was 47 years old and did a hysterectomy. He was in total shock by the mess that was discovered during my surgery. My organs were in a mass of tumors and growths which explained everything. The pathology report was like a novel. I think he was in complete shock when he discovered the mess that my insides were in. Thank goodness he removed everything he possibly could. I was finally able to convince someone that things in me just weren’t right. So this only proves that we are all different to some degree and not everything works for everyone. Plus, I wasn’t being a whiney cry baby but instead was legitimately a total wreck. So why acetaminophen does nothing for me is still a mystery but again, Noone listens to me.
It works ideally used as fever reduction. No off the self pain med such as ibuprofen should be used daily because of adverse impact. Its safer to treat chronic pain with low dose opioids, or fentanyl in severe cases.
Since fentanyl was leveraged into its role of the latest and greatest crack epidemic its been viewed very poorly. It really is a true public scourge. But when prescribed and used correctly by chronic pain sufferers, they can function normally physiologically and mentally.
After heart surgery last year, Tylenol was prescribed for pain. My pain was already minimal without Tylenol. Tylenol had no benefit for pain. I took it at night before bed to avoid pain and for a good night’s sleep. I had very heavy sweating during the night. The bed and sheets were soaked. At first didn’t know why. The suspected maybe Tylenol. Then did a few tests taking Tylenol before bed versus not. It was the Tylenol causing the sweats. I’ve not found any online evidence of this.
Tylenol has never given me any pain relief. Not even the slightest. I’m in the hospital right now and they were giving me almost a gram of Tylenol per dose and nothing. I got them to take me off it. No use in taking it if it doesn’t do anything for the pain.