The Endocannabinoid System

The Endocannabinoid System (ECS) is present in all living vertebrates and is thought to have evolved 500 million years ago. Understanding the ECS is fundamental in understanding the therapeutic actions of cannabis.

The ECS was discovered in the 1980s and 1990s as an important neuromodulatory system maintaining homeostasis and consists of endocannabinoids, cannabinoid receptors, and enzymes responsible for the synthesis and degradation of endocannabinoids. Researchers have described the endocannabinoid system as the most complicated and most ubiquitous signalling system in our bodies.

The ECS is involved in a number of physiological functions, disease states and important regulatory functions both in the central and peripheral nervous systems and in peripheral organs. It has an important role as a modulator in the regulation of inflammation, pain, sleep, mood, memory, appetite, reproduction and neurotransmission. 

The three components of the ECS are:

  • Cannabinoid receptors; found on the surface of cells

  • Endocannabinoids; small molecules that activate cannabinoid receptors

  • Metabolic enzymes; that break down endocannabinoids after they are used

Cannabinoid Receptors
The two primary cannabinoid receptors that have been identified are CB1 and CB2 which are both G-protein, coupled receptors, found on presynaptic neurons. G-protein coupled receptors detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular response.

CB1 receptors are the most abundant receptors in the brain. CB2 are more abundant outside of the nervous system in the peripheries. 

Cannabinoids are a class of biological compounds that bind to the cannabinoid receptors.


Endocannabinoids are naturally produced molecules in the body that are widespread and versatile and bind to cannabinoid receptors.

Endocannabinoids are neuromodulators, released by post-synaptic neurons, and bind to the presynaptic CB1/2 receptors to moderate the release of neurotransmitters, such as GABA, glutamate, and dopamine. Retrograde signalling permits them to regulate signalling activity across a wide range of physiological functions.

Our two major endocannabinoids are anandamide and 2-AG and are synthesised on demand.

Metabolic enzymes

Enzymes are present for the biosynthesis and degradation of endocannabinoids. Such enzymes quickly destroy endocannabinoids within the ECS once they are used. 
Cannabis exerts its effects, in part, by its molecular similarities to our own endocannabinoids.
A phytocannabinoid is a molecule synthesised by plants. There are 113 known phytocannabinoids in the cannabis plant. The most commonly known and widely studies are CBD and THC.  
Phytocannabinoids are concentrated in the glandular trichomes of the unfertilised female cannabis flower. They have molecular similarities to 2AG and anandamide, and therefore are able to directly interact with our own endogenous endocannabinoid system. 
Molecules like cannabinoids and other neurotransmitters rarely interact with only one receptor type; they often interact with many. So while plant cannabinoids may activate the same cannabinoid receptors as endocannabinoids but they also interact with several other receptors and therefore have distinct effects.


Disrupted endocannabinoid signalling has been associated with many disorders, including diabetes, hypertension, infertility, liver disease, migraines, IBS and chronic pain conditions such as fibromyalgia. 

Here at the Primary Care Cannabis Network, we want to make it that much easier for GPs to be kept up-to-date; by providing key insights, recent developments and providing a platform for discussion.  

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