The endocannabinoid system explained: signals in the body

The nervous system is an important area of endocannabinoid-system research; the illustration does not show its complete distribution.

The endocannabinoid system is a signalling system within the body. Its central components include particular messenger molecules, receptors and enzymes involved in their synthesis and breakdown. Here, ‘endo’ means originating within the body itself. A cannabis plant is therefore not required for this system to exist. An example of communication between nerve cells helps explain how it works.

An overview of the main components

Endocannabinoids are lipid-like messenger molecules produced by the body. Two particularly well-studied examples are anandamide and 2-arachidonoylglycerol, abbreviated to 2-AG. In 1992, Devane and colleagues described anandamide as a brain-derived substance that binds to the cannabinoid receptor. Read the original anandamide publication.

In 1995, Sugiura and colleagues also investigated the binding of 2-AG to cannabinoid receptors. Both molecules belong to the same field of research but are chemically distinct. Read the original paper on 2-AG.

Receptors are targets at which an appropriate binding interaction can influence a cellular response. The classical cannabinoid receptors include CB1 and CB2. Enzymes help limit the duration of a signal by breaking down its messenger molecules.

CB1 and CB2 are not simple on–off switches

The CB1 receptor is important in the example below: on the sending side of a nerve-cell connection, it can influence the release of messenger molecules. CB2 was molecularly characterised as another cannabinoid receptor in 1993; the original investigation found a different distribution pattern from the previously known receptor. Read the CB2 publication by Munro and colleagues.

Simplifications such as ‘CB1 only in the brain’ and ‘CB2 only in the immune system’ are too rigid. A specific statement depends on the tissue, cell type and investigation. Binding to a receptor also does not automatically establish a particular perceptible or therapeutic effect.

An example: how nerve cells communicate backwards

At a synapse, a sending nerve cell normally releases messenger molecules to which a receiving cell responds. In certain situations, endocannabinoids can provide feedback in the opposite direction. This is called retrograde signalling.

1. The receiving nerve cell becomes active.

2. An endocannabinoid signal travels back to the sending side.

3. There, it can activate CB1 receptors.

4. This can temporarily reduce the release of another messenger molecule.

5. Breakdown of the signalling substances involved helps limit the feedback.

In 2001, Wilson and Nicoll demonstrated this kind of backward signalling at hippocampal synapses. They investigated temporary suppression of GABA-mediated signalling. Read the original study of retrograde signals.

This example describes an investigated mechanism, not every function of the endocannabinoid system. It also corrects a common simplification: CB1 activation does not invariably mean that more neurotransmitters are released.

Why enzymes are just as important as receptors

A signal needs to be able to end as well as begin. Fatty acid amide hydrolase, abbreviated to FAAH, plays an important role in breaking down anandamide. In 1996, Cravatt and colleagues reported the molecular characterisation of an enzyme that acts on substances including anandamide. Read the original FAAH paper.

Monoacylglycerol lipase, often called MAGL or MGL, is among the enzymes involved in 2-AG breakdown. Dinh and colleagues investigated its contribution to 2-AG inactivation in 2002. Read the investigation of 2-AG breakdown. Considering enzymes illustrates why a signalling system cannot be explained solely by the number of its receptors.

Distinguishing the body's own cannabinoids from plant-derived cannabinoids

Anandamide and 2-AG are endocannabinoids. CBD, CBG and CBN, by contrast, are discussed as plant-derived cannabinoids or cannabinoids associated with plant material. Similar names do not make these substances interchangeable. Nor does the existence of the endocannabinoid system mean that everyone needs additional cannabinoids.

Without a precisely defined measurement, terms such as ‘balance’ or ‘supporting the system’ are not clear scientific evidence of an effect. A claim about a finished product would need to relate to its particular composition and an appropriately investigated question.

Explore the basics further

Our endocannabinoid-system information page provides a broader overview. The articles What is CBD? and What is CBG? introduce individual compounds.

Please note: this article explains biological principles. It provides no diagnosis, treatment recommendation or assurance of efficacy for cannabinoid products.

Sources and further evidence

The following sources are already linked in the text. The short English descriptions are provided for orientation; the original titles and bibliographic details are available in the linked publications.

• Devane WA et al. (1992): isolation and structure of an endogenous ligand for the cannabinoid receptor. PMID 1470919.

• Sugiura T et al. (1995): 2-arachidonoylglycerol as a possible endogenous cannabinoid-receptor ligand in the brain. PMID 7575630.

• Munro S et al. (1993): molecular characterisation of a peripheral cannabinoid receptor. PMID 7689702.

• Wilson RI et al. (2001): endocannabinoids and retrograde signalling at hippocampal synapses. PMID 11279497.

• Cravatt BF et al. (1996): molecular characterisation of an enzyme that breaks down fatty acid amides. PMID 8900284.

• Dinh TP et al. (2002): monoacylglycerol lipase and endocannabinoid inactivation in the brain. PMID 12136125.