Inside the Endocannabinoid System: Receptors, Ligands, Enzymes

Four papers, five years, one system on the record

CB1 and CB2: two receptors, two neighbourhoods

CB1 came first, and the way it arrived matters. In 1990, Matsuda and colleagues cloned a cannabinoid receptor and expressed the cloned sequence in cells [1]. Before that work, the action of plant-derived cannabinoids pointed towards a receptor. After it, there was a molecular target to work with rather than one inferred from what a plant compound did in a body [1]. The receptor was named for those plant compounds, which is the honest origin of the whole vocabulary: chemistry chose the name. CB1 sits chiefly in the central nervous system, and within it across many brain regions.

Three years later, the map got bigger. Munro and colleagues published the molecular characterisation of a second receptor and described it as peripheral rather than central, with its main association in immune tissues [2]. CB2 was the name. The finding carried a plain implication. A system with a receptor on immune tissues and in cells outside the central nervous system is not a brain system with an odd side note. It runs wider than that.

So: two receptors, two different neighbourhoods, three years apart. They are also the two components of this system that have been described in real depth. That is not the same as saying they are the whole system. The 1990 and 1993 papers describe two receptors. They do not claim to describe every receptor a body-made cannabinoid might reach.

There is a timing detail worth keeping in mind. Cannabis chemistry ran decades ahead of cannabis biology. Compounds had been isolated and described long before anyone could point to where they landed. That gap closed in the first half of the 1990s, in a run of about five years [1][2][3][4]. Four papers, two receptors, two ligands.

Cloning and expression sound like lab housekeeping, so it is worth unpacking once. Cloning a receptor means reading and copying the sequence that codes for it. Expressing that sequence in cells means building the receptor somewhere it can be tested directly. Do both, and a receptor stops being a reasonable guess about how a plant compound works. It becomes a protein with a sequence, an address, and a set of experiments that other groups can repeat [1]. That is the difference between 1989 and 1990.

Ten numbered notes on the body's own cannabinoids

1. Anandamide was the first one isolated. Devane and colleagues described a brain constituent that bound to the cannabinoid receptor [3]. The weight sits in the word brain: the ligand came from tissue, not from a plant, so the receptor cloned two years earlier had something of its own to respond to.
2. The name followed the chemistry. Anandamide borrows the Sanskrit ananda, which is unusual company for a fatty acid derivative. The structure and the binding were published first, and the name is the part most people remember [3].
3. 2-AG came second. In 1995, Sugiura and colleagues reported 2-arachidonoylglycerol from brain tissue and put it forward as a further candidate endogenous ligand at the cannabinoid receptor [4]. Candidate was the careful framing at the time, and careful framing has aged well.
4. Endogenous is the whole point. Both molecules are made inside the body. The system is called endocannabinoid for that reason, not because anyone had a plant in mind when the ligands turned up.
5. Anandamide is cleared mainly by fatty acid amide hydrolase, shortened to FAAH in most writing. Main route is the accurate phrasing, and it is the phrasing the literature keeps.
6. 2-AG is cleared mainly by monoacylglycerol lipase, or MAGL. Two ligands, two principal enzymes. Not interchangeable, and the pairing is one of the details that makes this system describable rather than vague.
7. Three kinds of parts, then: receptors, ligands, enzymes. Short explanations tend to mention the first two and drop the third, which leaves out how a signal gets removed again.
8. The 1992 and 1995 papers are three years apart, and both sit inside the same five-year stretch as the two receptors [1][2][3][4]. One decade, two halves: chemistry earlier, biology here.
9. Anandamide and 2-AG are the two the literature keeps returning to, not the full inventory. Further candidate ligands, and further enzymes, are still being characterised. The list stays open.
10. None of this is biochemistry vocabulary for its own sake. A receptor with a sequence, a ligand with a structure, an enzyme with a name: that is what turns a loose claim into something checkable.

GPR55 and the parts still marked open

Not every receptor in this conversation has a settled label. GPR55 is an orphan G-protein-coupled receptor. Orphan means what it sounds like: the natural signalling partner has not been firmly established. Researchers have examined it alongside CB1 and CB2, and some have argued it belongs in the same family. That proposal is contested. GPR55 holds no formal classification as a cannabinoid receptor, and classing it as one goes further than the evidence does. It sits in an honest middle position: examined, discussed, unresolved. We are comfortable leaving it there.

The same restraint applies to the rest of the map. CB1 and CB2 are described in depth. Anandamide and 2-AG are described in depth. FAAH and MAGL are named as the main clearance routes for those two ligands. Past that, further candidate ligands and further enzymes remain under characterisation, which is a normal state for a system that has only been on the record since 1990. A field that starts in 1990 is young next to most of the pharmacology around it.

One more thing worth saying plainly. The link between this system and the cannabis plant is a matter of chemistry, not of marketing. The receptor cloned in 1990 was called a cannabinoid receptor because of what plant-derived cannabinoids do at it [1]. The plant came into the story as a tool for finding the receptor. The receptor then turned out to have ligands of its own, made in the body, and enzymes to clear them again.

Since 2014: what a batch report can show

Cibdol has been working with cannabinoids since 2014, long enough to have watched a lot of confident claims come and go. Our working rule is short: state what can be measured, then show the measurement. Every batch is documented and comes with third-party certificates, so the cannabinoid content of a bottle is something you can read rather than take on trust. That does not stretch to the biology on this page. A certificate says what is in an extract. It says nothing about receptors, ligands, or enzymes, and we would rather draw that line than blur it. The same standard applied in 2014 and applies now. Research on this system continues, and when the evidence moves, the writing here moves with it.