PainRelief.com Interview with:
Alex Straiker Ph.D.
Associate Research Scientist, Psychological and Brain Sciences
Adjunct Instructor, Psychological and Brain Sciences
Department of Psychological and Brain Sciences
Gill Institute for Neuroscience, Indiana University
Bloomington, IN 47405, USA

PainRelief.com: What is the background for this study?

Response: Acetaminophen has been used to relieve pain since the late 19th century and became available around the world during the 1950s and 1960s. In the United States, it’s known as Tylenol (introduced in 1955), while in most other countries it’s referred to as paracetamol.

It is considered generally safe and remains one of the most widely used medications in the world. However, it still contributes to a significant number of deaths due to liver failure. In fact, in many countries, acetaminophen-related toxicity is the leading cause of acute liver failure.

What’s surprising is that, despite its long history and widespread use, we still don’t fully understand how acetaminophen works.

Scientists have proposed several mechanisms of action involving serotonin pathways and cyclooxygenase (COX) enzymes.  Several lines of evidence point to the body’s natural cannabis-like chemicals, called endocannabinoids.

PainRelief.com: What are the main findings?

Response: Generally, it’s believed that increasing endocannabinoid levels helps relieve pain.

But our study uncovered something unexpected: acetaminophen actually blocks an enzyme responsible for producing one of these endocannabinoids, called 2-AG. In other words, it may lower endocannabinoid levels to reduce pain—challenging the common assumption that more endocannabinoids always mean less pain.

Our research suggests that the relationship between endocannabinoids and pain is more complex than previously thought.

It’s possible that Tylenol relieves pain not by boosting these natural chemicals, but by reducing one of them. This new perspective could reshape our understanding of pain management and potentially lead to the development of more effective, targeted pain medications in the future.

PainRelief.com: What should readers take away from your report?

Response: Our study reveals an unexpected mechanism behind the action of a widely used drug. While this discovery is just one small piece of a much larger puzzle, it offers important insights.

We specifically examined short-term thermal pain—just one of many different types of pain. It’s very likely that different forms of pain are driven by distinct biological mechanisms.

Even so, our findings highlight the enzyme diacylglycerol lipase alpha (DAGLa)—which produces the endocannabinoid 2-AG—as a potential new target for pain treatment.

PainRelief.com: What recommendations do you have for future research as a result of this study?

Response: Our finding suggests that diacylglycerol lipase alpha—the enzyme responsible for producing 2-AG and blocked by acetaminophen—may be a promising target for relief of the sort of pain that acetaminophen works well for.  If we keep exploring this path, it could lead to a new class of pain relief drugs.

Citation: 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, Alex Straiker,
Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: Implications for nociception,
Cell Reports Medicine,2025,102139,ISSN 2666-3791,
https://doi.org/10.1016/j.xcrm.2025.102139

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Last Updated on May 25, 2025 by PainRelief.com