Updated: Mar 29
For many people, popping a couple of Tylenol® tablets is a great way to get rid of some aches and pains. But for years we didn’t have a full understanding of its exact pathway and mechanism of action. What researchers have recently found is that there’s a strong connection between acetaminophen (the chemical name for Tylenol®) and the endocannabinoid system (1). In fact, it seems that the endocannabinoid circuitry is vital to the pain-relieving impact of acetaminophen.
You might be thinking the endo- WHAT?!?! Well, “endo-” means within and “cannabinoids” are chemicals found in cannabis. So, the endocannabinoid system is a physiological system within our bodies that has neurotransmitters, receptors and enzymes related to cannabis. Now you might be wondering why you’ve never heard of the endocannabinoid system before. It’s because it was identified in 1992 and scientists are learning more about it with each passing year. At this point, it is understood that the endocannabinoid system likely impacts all aspects of our physical functioning because it is comprised of the circulating neurotransmitters anandamide and 2-AG and their receptors (CB1 and CB2) which are found throughout the body including the brain. Anandamide (which was named for the Sanskrit word “anada” meaning “bliss”) is known to interact with pain pathways such that higher levels of anandamide are correlated with less pain (2).
When acetaminophen (aka Tylenol®) is digested and broken down, the chemical compound AM404 is formed and circulates within the body. And guess what!?!
AM404 increases the concentration of anandamide circulating around the nerves by interfering with its re-uptake. This allows anandamide to continue its action on its receptor sites for an extended period of time. Scientists also found that AM404 can bind to the CB1 receptors of the endocannabinoid system and have an effect on pain reactions. However, if the CB1 receptors are blocked or deficient for some reason, acetaminophen doesn’t work to decrease pain even though it blocks the re-uptake of anandamide.
Scientists also learned that a key enzyme of the endocannabinoid system called FAAH not only breaks down anandamide, it also metabolizes acetaminophen. So, when there’s no FAAH or it isn’t working properly acetaminophen’s metabolite AM404 isn’t produced and we don’t get the expected pain relief.
What’s the take home message?
First, taking Tylenol® interferes with the re-uptake of anandamide (your body’s “bliss” neurotransmitter), allowing it to hang around longer at the receptor site, reducing pain. And it gives anandamide a better chance to impact your endocannabinoid system.
Second, if there’s dysfunction in the endocannabinoid system either at the receptor site or with the enzyme FAAH, acetaminophen won’t relieve pain.
So, for people who say Tylenol® doesn’t work for them, could it be that there’s a deficiency in the endocannabinoid system? Is it possible that acetaminophen for short periods of time can support your endocannabinoid system by boosting anandamide?
The answers to these question (and many others related to pain) remain to be seen as we continue to learn about the many aspects of the endocannabinoid system.
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Klinger-Gratz, PP, et al. (2018). Acetaminophen relieves inflammatory pain through CB1 cannabinoid receptors in the rostral ventromedial medulla. Journal of Neuroscience, 38(2), 322-334.
Habib, AM, et al. (2019). Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. British Journal of Anaesthesia, 123(2), e249-e253.