Indianapolis, Indiana – A team of researchers at Indiana University has made a breakthrough in understanding how one of the most widely used pain relievers in the world—acetaminophen—actually works. Their discovery could reshape the pharmaceutical industry’s approach to designing more effective and safer medications for pain management.
Acetaminophen, commonly known by brand names like Tylenol or paracetamol, has been used for decades to treat pain and reduce fever. Despite its long history and widespread use—more than 60 million Americans take it each week—scientists have never been fully sure exactly how the drug alleviates pain. But that might be about to change.
A new study led by Michaela Dvorakova, a postdoctoral researcher at Indiana University’s Gill Institute for Neuroscience and the Department of Psychological and Brain Sciences, along with research scientist Alex Straiker, has uncovered a previously unknown mechanism by which acetaminophen reduces pain. Their findings, recently published in Cell Reports Medicine, suggest that acetaminophen acts by inhibiting an enzyme responsible for producing a compound called 2-arachidonoyl glycerol (2-AG)—a type of endocannabinoid made naturally by the human body.
Read also: Marion students’ visual and performing arts take center stage at the all-city art show this weekend
Endocannabinoids are molecules that help regulate various functions in the body, including pain, mood, and appetite. They interact with CB1 receptors in the brain, the same receptors that respond to THC, the psychoactive ingredient in cannabis. For years, scientists believed that increasing endocannabinoid levels led to pain relief. However, Dvorakova and Straiker’s research challenges that assumption.
“There are hypotheses, but we still don’t know precisely how it works,” said Dvorakova. “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 leads to decreased pain.”
This finding not only deepens our understanding of how acetaminophen works but could also pave the way for the development of new painkillers that target this same mechanism—without the potentially dangerous side effects of current medications.
Acetaminophen is generally safe at recommended doses, but in large amounts it can cause serious liver damage. Each year, about 500 deaths in the U.S. are linked to acetaminophen toxicity, and it’s one of the leading causes of liver transplants globally. Understanding the exact biological target of the drug could help scientists design alternatives that avoid these risks altogether.
“If you don’t know what the target is, you can’t design an alternative,” said Straiker. “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.”
Straiker acknowledged that their findings might be met with skepticism, especially because for decades, the prevailing belief has been that activating CB1 receptors was the primary way to achieve pain relief through endocannabinoids. Changing long-held views in science is no easy task.
“It can be hard to break through that dogma,” Straiker said.
The study brought together a diverse group of collaborators from institutions across the U.S. and China, including scientists from Peking University, the University of Texas at Austin, and Scripps Research Institute. This multidisciplinary approach helped confirm and strengthen the findings across multiple models and methods.
Going forward, the Indiana University team plans to extend their research to other over-the-counter pain relievers like ibuprofen and aspirin. By exploring whether these drugs also interact with endocannabinoids or similar enzymes, they hope to build a broader understanding of how common painkillers work—and how they can be improved.
The discovery opens a new chapter in pain medicine. With a clearer picture of how acetaminophen operates at the molecular level, scientists are now better equipped to design targeted, less harmful medications. For millions of people who rely on pain relievers daily, this could mean safer and more effective options in the not-so-distant future.
As research continues, the implications of this study stretch beyond just one drug. It challenges decades of assumptions and could be the foundation for a new generation of pain therapies—grounded not only in effectiveness but also in safety.
