The Endocannabinoid System

The brain's own cannabis-like signalling system: anandamide and 2-AG, CB1 and CB2 receptors, messages that travel backwards across synapses — and what THC and CBD actually do.

The story of the endocannabinoid system began, like that of endorphins, with a plant. In 1964 the Israeli chemist Raphael Mechoulam and colleagues identified THC (delta-9-tetrahydrocannabinol) as the main psychoactive compound in cannabis. In 1988 researchers found a specific receptor for it in the brain — CB1, now known to be one of the most abundant G-protein-coupled receptors in the brain. A second receptor, CB2, is found mainly on immune cells.

The body's own cannabinoids

The brain doesn't make receptors for plants. In 1992 Mechoulam's group identified the first natural ligand and named it anandamide, from the Sanskrit ananda, "bliss". A second, 2-AG, was found soon after and is more abundant. Unlike most transmitters, endocannabinoids aren't stored in vesicles; they are made on demand from fats in the cell membrane.

Messages that go backwards

The system's most unusual feature is retrograde signalling. When a postsynaptic neuron is strongly activated, it makes endocannabinoids, which travel backwards across the synapse to CB1 receptors on the presynaptic terminal and reduce its transmitter release. This acts as a feedback "volume control" on both excitatory and inhibitory synapses.

What it does

Endocannabinoids influence pain, appetite, stress and anxiety responses, memory and the extinction of fear, motor control and nausea. They may contribute to the "runner's high".

THC and CBD

THC activates CB1 receptors everywhere at once, far more broadly than natural signals would, which explains the effects of cannabis: altered perception and time, increased appetite ("the munchies"), impaired short-term memory and coordination, and in some people anxiety or paranoia. Heavy use in adolescence is associated with an increased risk of psychosis in vulnerable people. CBD (cannabidiol) does not strongly activate CB1 and isn't intoxicating; a purified CBD medicine (Epidiolex) is approved for certain severe childhood epilepsies, while many commercial health claims for CBD lack good evidence.