The endocannabinoid system
The body's own cannabis-like signalling system: small fats made on demand that tune nerve signals, appetite, stress, pain and immunity.
Endocannabinoids are lipid messengers that the body makes when it needs them and breaks down quickly. They act on CB1 receptors, mostly in the nervous system, and CB2 receptors, mostly on immune cells. THC and other cannabinoid drugs borrow this system, which explains both their medical uses and their side effects.
Endocannabinoids: synthesis and breakdown
Anandamide is formed from a membrane phospholipid precursor, mainly through the enzyme NAPE-PLD. 2-AG is made in two steps: phospholipase C produces diacylglycerol, and diacylglycerol lipase (DAGL) turns it into 2-AG. Both signals are short-lived. FAAH, found on intracellular membranes of the postsynaptic neuron, hydrolyses anandamide; MAGL, located in presynaptic terminals, hydrolyses 2-AG after it has acted. Both reactions release arachidonic acid, which links this system to prostaglandin formation in inflammation.
CB1 and CB2 receptors
Both receptors are G protein-coupled. CB1 is abundant in the brain and on peripheral nerve terminals, with especially high levels on some presynaptic GABA interneurons. CB2 is found mainly in peripheral tissues and immune cells, such as B lymphocytes and natural killer cells, and at low levels in the brain. Some ligands favour particular downstream pathways (biased agonism).
Physiological roles
- Synapses: retrograde signals that briefly damp transmitter release and shape synaptic plasticity.
- Stress: endocannabinoid release after stress helps end the stress response; the amygdala is a key hub for anxiety and mood effects.
- Feeding: hypothalamic levels rise with fasting and fall with feeding; leptin suppresses this signalling.
- Pain: actions in the periaqueductal grey and periphery modulate pain.
- Reward: signalling in the ventral tegmental area contributes to the rewarding effect of food and exercise.
- Other roles: nausea and vomiting circuits, sleep, memory, movement, bone and immune function.
Therapeutic uses of cannabinoids
Dronabinol (synthetic THC) and nabilone, a similar synthetic compound, treat chemotherapy-induced nausea and vomiting; dronabinol is also used for appetite and weight loss in HIV/AIDS. Purified cannabidiol is approved for seizures in Lennox-Gastaut and Dravet syndromes. Nabiximols, a THC plus CBD oromucosal spray, is licensed in some countries for MS spasticity; reviews show a small improvement in patient-reported spasticity but not on objective scales. For chronic pain, reviews show at most a small benefit with more side effects.
Drug development: CB1 antagonists and enzyme inhibitors
Rimonabant, a CB1 inverse agonist, produced modest weight loss and was approved in the EU for obesity, but users had more anxiety, depression and suicidality; because of these concerns it never gained FDA approval. Research has since turned to peripherally restricted CB1 antagonists for obesity and metabolic disease, aiming to avoid psychiatric effects. Another strategy is to slow endocannabinoid breakdown: FAAH inhibitors raise anandamide, MAGL inhibitors raise 2-AG. Several have entered clinical trials, but none is approved.
Test yourself
Think of the answer, then tap the question to see it.
Which enzyme mainly degrades anandamide, and which mainly degrades 2-AG?
Fatty acid amide hydrolase (FAAH) degrades anandamide; monoacylglycerol lipase (MAGL) degrades 2-AG.
Why are endocannabinoids called retrograde messengers?
They are made by the postsynaptic neuron and travel backwards to presynaptic CB1 receptors, where they reduce transmitter release.
Why was rimonabant abandoned despite causing weight loss?
Blocking central CB1 receptors increased anxiety, depression and suicidality.
Where are CB2 receptors mainly expressed?
In peripheral tissues and immune cells, such as B lymphocytes and natural killer cells, with low levels in the brain.
Example drugs
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Cannabis and Cannabinoids (PDQ®)–Health Professional Version (National Cancer Institute, 2026); Cannabis (Marijuana) and Cannabinoids: What You Need To Know (National Center for Complementary and Integrative Health (NCCIH), 2026).
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Representative model, for educational purposes only.