CB1 and CB2 are two G-protein coupled receptors in the endocannabinoid system. CB1 sits on neurons in the brain and spinal cord. CB2 sits on immune cells. THC binds both receptors. CBD binds both with low affinity.
What the receptors are
Both are seven-transmembrane receptors that couple to Gi/o proteins. Activation lowers cyclic AMP inside the cell. CB1 was cloned in 1990 from rat brain. CB2 was cloned in 1993 from human spleen. The genes are CNR1 on chromosome 6 and CNR2 on chromosome 1.
Endogenous ligands
Two lipid messengers bind these receptors. 2-arachidonoylglycerol (2-AG) is a full agonist at CB1 and CB2. Anandamide is a partial agonist with lower efficacy. Both are made on demand and broken down by enzymes: FAAH for anandamide, MAGL for 2-AG.
Where CB1 sits
CB1 density is high in the cortex, hippocampus, basal ganglia, and cerebellum. Levels are low in the brainstem, so cannabinoids do not halt breathing at typical doses. CB1 also appears in liver, fat tissue, and peripheral nerves.
Where CB2 sits
CB2 shows up on B cells, T cells, macrophages, and microglia. Spleen and tonsil tissue carry high counts. CB2 activation does not produce the psychoactive effects tied to CB1.
THC and CBD at the receptors
THC is a partial agonist at CB1 and CB2. Its binding affinity sits in the low nanomolar range, with Ki near 40 nM at CB1 in common assays. CBD has low affinity, with Ki values above 10,000 nM in many assays. CBD acts as a negative allosteric modulator at CB1 in some studies. That means it changes receptor response without blocking the site THC uses. At CB2, CBD acts as an inverse agonist in several cell models. Results differ by assay.
Effects linked to each receptor
- CB1: memory, appetite, pain signaling, motor control, mood, and the high from THC.
- CB2: immune cell migration, cytokine release, inflammation, and pain sensitization in tissue.
Some CB2 signals come from cells in the spinal cord and dorsal root ganglia. The receptor plays a role in pain modulation without brain involvement.
What is not settled
Receptor counts vary by tissue, species, and method. CBD pharmacology shifts with dose and cell type. No human study has fixed a single mechanism for CBD at these receptors.