Endocannabinoids: The Cannabinoids The Body Builds Itself

One word, two named molecules

The prefix carries most of the meaning. Endo comes from endogenous, which means made inside the organism rather than taken in from outside. The second half of the word points at the receptors involved: the cannabinoid receptors. Put the two halves together and you have a compact description of a cannabinoid the body produces itself.

Two of these molecules have names that keep coming up.

Anandamide was the first to be described. Devane and colleagues isolated it from brain tissue in 1992 and recorded its binding to the cannabinoid receptor [1]. That report is the starting point for everything written about endocannabinoids since, and it is worth noting how narrow it is: a constituent of brain tissue, isolated, structurally described, shown to bind.

Then came 2-arachidonoylglycerol, almost always shortened to 2-AG. Sugiura and colleagues identified it in brain tissue in 1995 and read it as a possible endogenous ligand for the cannabinoid receptor [2]. Three years separate the two publications [1][2].

So the pair is anandamide and 2-AG. Both are lipids, which is to say fat-like molecules rather than water-soluble ones. Once released, both act at cannabinoid receptors on cells close by [1][2]. Beyond the pair, further related lipids have been proposed as endocannabinoids and remain under study, which is the honest way to describe a list that is not closed.

One structural detail explains a lot of what follows. Anandamide is an amide. 2-AG is a glycerol ester. Different chemistry, different handling: each molecule has its own degrading enzyme, so the two can be regulated independently of one another. Anandamide is hydrolysed by fatty acid amide hydrolase, the enzyme Fowler and colleagues set out in their 2001 review [3]. For 2-AG, monoacylglycerol lipase is the main route. Same receptor family at one end, separate machinery at the other.

The sequence, point by point

1. 1992, the first description. Devane and colleagues isolate anandamide from brain tissue and describe a brain constituent that binds to the cannabinoid receptor [1]. This is the first named endocannabinoid in the literature.
2. 1995, the second name. Sugiura and colleagues identify 2-arachidonoylglycerol in brain tissue and read it as a possible endogenous cannabinoid receptor ligand [2]. Three years after the anandamide report, the pair is on record [1][2].
3. Two different bonds. Anandamide is an amide. 2-AG is a glycerol ester built on glycerol. The distinction is not cosmetic, because the bond determines which enzyme can take the molecule apart again.
4. Two different enzymes. Because the chemistry differs, each has its own degrading enzyme. That separation is what allows the two endocannabinoids to be regulated independently rather than as a single pool.
5. Where they act. After release, anandamide and 2-AG reach cannabinoid receptors on nearby cells [1][2]. Local, then, rather than distributed the way a classic bloodstream hormone would be.
6. Clearing anandamide. Hydrolysis by fatty acid amide hydrolase is the route described for anandamide, and Fowler and colleagues laid out the biochemistry and pharmacology of that enzyme in a 2001 review [3].
7. Clearing 2-AG. Monoacylglycerol lipase is the main route for 2-AG. Different name, different enzyme, consistent with the ester chemistry rather than the amide chemistry.
8. An enzyme as a target. The same 2001 review by Fowler and colleagues reads fatty acid amide hydrolase as a pharmacological target, which is why the enzyme keeps appearing in later work [3].
9. The open column. Additional related lipids have been proposed as endocannabinoids and are still under study. Two molecules are named with confidence; the rest of the list is a research question, not a finished inventory.

Why the two are not one thing

It is tempting to file anandamide and 2-AG together and stop there. The word covers both, they meet the same receptor family [1][2], and they turn up in the same paragraph of most explanations. Look at the chemistry and the picture separates. An amide and a glycerol ester are taken apart by different enzymes, which means the body can raise or lower one without automatically doing the same to the other. Independent regulation is the practical consequence of a structural difference.

The enzymes are named, and that matters more than it sounds. Fatty acid amide hydrolase has been reviewed as a subject in its own right, biochemistry and pharmacology together, by Fowler and colleagues in 2001 [3]. Monoacylglycerol lipase sits on the other side, as the main route for 2-AG. If you want the molecule and the research around it in more detail than fits here, our separate entry on 2-AG goes through both at length.

The record in short form:

• Anandamide. First described. Isolated from brain tissue in 1992, with binding to the cannabinoid receptor recorded by Devane and colleagues [1].
• 2-AG. Identified in 1995 in brain tissue and read as a possible endogenous cannabinoid receptor ligand by Sugiura and colleagues [2].
• Chemistry. Amide for anandamide, glycerol ester for 2-AG.
• Clearing anandamide. Fatty acid amide hydrolase, the enzyme reviewed by Fowler and colleagues in 2001 [3].
• Clearing 2-AG. Monoacylglycerol lipase, described as the main route.
• Site of action. Cannabinoid receptors on nearby cells, for both molecules [1][2].
• Still open. Further related lipids proposed as endocannabinoids, under study.

What the three cited papers cover

Brain tissue, 1992 and 1995

Both foundational reports come from brain tissue. Devane and colleagues worked on an isolated brain constituent in 1992 and described its structure along with its binding to the cannabinoid receptor [1]. Sugiura and colleagues followed in 1995 with 2-arachidonoylglycerol, presented as a possible endogenous ligand for that receptor in brain [2]. Read the wording closely and you notice the caution in the second one: possible. That is how a new candidate molecule enters the literature, and it is a useful reminder that a name on a list is not the same as a mapped role. What these two papers fix is identity, structure and receptor binding [1][2]. Anything broader belongs to the work that came afterwards.

One enzyme, one review, 2001

The third citation shifts the focus from the molecules to the machinery. Fowler and colleagues reviewed fatty acid amide hydrolase in 2001, covering its biochemistry and its pharmacology, and reading the enzyme as a pharmacological target [3]. Anandamide hydrolysis is the reaction at the centre of it. For 2-AG, monoacylglycerol lipase is the main route, and that difference in enzymes is what keeps the two endocannabinoids on separate tracks. We have worked with cannabinoids since 2014, and the approach to a page like this is the same as the approach to a batch report: name the source, keep the year attached, and say plainly where the record stops. Three papers, two molecules, a short list of enzymes with names. The rest is still being written.