CB1R (gene symbol CNR1) is encoded on chromosome 6 in humans and belongs to the Class A (rhodopsin-like) family of G protein-coupled receptors (GPCRs). It couples predominantly to inhibitory Gi/o proteins, meaning activation generally suppresses cyclic AMP production and reduces neuronal excitability. Receptor density is particularly high in the basal ganglia, cerebellum, hippocampus, cerebral cortex, and spinal cord dorsal horn, though CB1R is also expressed at lower levels in peripheral tissues including the liver, adipose tissue, and the gastrointestinal tract.
Endogenously, CB1R is activated by the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), both of which are synthesised on demand from membrane phospholipid precursors and act as retrograde messengers , travelling backwards across synapses to suppress presynaptic neurotransmitter release. This retrograde signalling mechanism plays a described role in short- and long-term synaptic plasticity, including depolarisation-induced suppression of inhibition (DSI) and depolarisation-induced suppression of excitation (DSE).
Exogenous cannabinoids interact with CB1R with varying affinity and efficacy. Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of Cannabis sativa, acts as a partial agonist at CB1R. Cannabidiol (CBD), by contrast, shows low direct binding affinity for CB1R and has been characterised in preclinical work as a negative allosteric modulator, altering receptor conformation without acting as a classical agonist or antagonist. The precise functional consequences of this allosteric interaction remain an area of active research.
Some researchers have proposed that reduced CB1R signalling tone , sometimes called "endocannabinoid deficiency" , may contribute to certain physiological states, but this remains a hypothesis. As of 2024, no clinical diagnostic criterion for such a condition has been established, and the evidence base draws largely on preclinical and small observational studies. Any such framing should be read as speculative rather than settled science.
In Australia, substances that act directly on CB1R with agonist activity (including synthetic cannabinoid receptor agonists) are subject to scheduling under the Poisons Standard (the Standard for the Uniform Scheduling of Medicines and Poisons, or SUSMP). Many synthetic CB1R agonists are listed as Schedule 9 Prohibited Substances. THC-containing preparations are Schedule 8 Controlled Drugs, accessible only via prescription under the Therapeutic Goods Administration (TGA) framework, including the Special Access Scheme (SAS) and Authorised Prescriber pathways.
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