How Acetaminophen (Paracetamol) Suppresses Endocannabinoids

…contrary to all expectations (and how this can lead to more effective acetaminophen-like pain relief, without the toxicity!

It’s well known that acetaminophen (international name: paracetamol, most well-known brand name in the US: Tylenol) is a mild painkiller and anti-fever agent; what’s not well understood is how it actually works.

Recently, a team of researchers (Dr. Michaela Dvorakova et al.) looked into this, and found something that was quite surprising, to understate it considerably.

That sounds like a clickbait headline (“and what they discovered will shock you!”) but well, we don’t do clickbait and our own headline covers it: acetaminophen suppresses endocannabinoids, when generally for painkilling purposes we want more endocannabinoids, not less.

Before we get into that, let’s take a moment to note some of the bad parts of acetaminophen’s safety profile, which is to say: it’s really not very safe.

Rather than repeat ourselves though, we’ll link to where we did a whole main feature about that, here: Before You Reach For That Tylenol…

Now, about acetaminophen and endocannabinoids

In the lead researcher’s words:

❝There are hypotheses, but we still don’t know precisely how it works. 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.❞

~ Dr. Michaela Dvorakova

You may be wondering: what’s 2-AG?

And the answer is that it’s 2-arachidonoyl glycerol, which is a cannabinoid naturally made by the human body (thus, endogenous cannabinoid, or usually written: endocannabinoid).

What the researchers found is that acetaminophen inhibits an enzyme that makes that endocannabinoid, namely, diacylglycerol lipase α (DAGLα) ← as in, this is the name of the enzyme that makes it.

Thus, inhibiting the enzyme means inhibiting endocannabinoid production. So, what gives, and why does this work as a painkiller, when it looks like it’s doing the opposite?

The researchers propose… Well, we’ll quote them:

❝This gives rise to the counterintuitive hypothesis that decreasing endocannabinoid production by DAGLα inhibition may be antinociceptive in certain settings.

Supporting this hypothesis, we find that diacylglycerol lipase (DAGL) inhibition by RHC80267 is antinociceptive in wild-type but not CB1 knockout mice in the hot-plate test.

We propose (1) that activation of DAGLα may exacerbate some forms of nociception and (2) a mechanism for the antinociceptive actions of acetaminophen, whereby acetaminophen inhibits a DAGLα/CB1-based circuit that plays a permissive role in at least one form of nociception.❞

Translating from sciencese: by stopping the endocannabinoid production, the body is triggered to engage a different, more effective method of killing pain.

You can read the paper in full here: Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: Implications for nociception

As for what the implications are? Per the researchers, it means that if we understand that inhibiting the enzyme DAGLα triggers a painkilling response, then new drugs can be designed to target DAGLα without the toxicity of acetaminophen.

So, keep an eye out for that, and you heard it hear first!

Want to learn more?

We’ve written quite a bit about pain management, including:

• How To Stop Pain Spreading
• How To Dial Down Your Pain
• Managing Chronic Pain (Realistically!)
• Get The Right Help For Your Pain
• The 7 Approaches To Pain Management
• Science-Based Alternative Pain Relief (When Painkillers Aren’t Helping, These Things Might)

Take care!