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.