Cannabinoid Pharmacology
The endocannabinoid system, CB1 and CB2 receptors, and the pharmacology of THC, CBD, and synthetic cannabinoids.
The Endocannabinoid System
The endocannabinoid system comprises lipid-derived retrograde messengers, their receptors, and biosynthetic/degradative enzymes. Unlike classical neurotransmitters, endocannabinoids are synthesized on demand from membrane phospholipids and signal retrogradely from the postsynaptic to the presynaptic neuron.
- Anandamide (AEA) -- partial CB1 agonist; synthesized by NAPE-PLD; degraded by FAAH
- 2-Arachidonoylglycerol (2-AG) -- full CB1 agonist; synthesized by DAG lipase; degraded by MAGL
Cannabinoid Receptors
| Receptor | Coupling | Distribution | Function |
|---|---|---|---|
| CB1 | Gi/Go | CNS (cortex, hippocampus, basal ganglia, cerebellum) | Inhibits presynaptic neurotransmitter release; modulates pain, mood, appetite, memory |
| CB2 | Gi/Go | Immune cells, spleen, microglia | Immunomodulation, anti-inflammatory effects |
CB1 activation reduces glutamate and GABA release through inhibition of presynaptic calcium channels, acting as a synaptic circuit breaker that prevents excessive excitation or inhibition.
Phytocannabinoids
Cannabis contains over 100 phytocannabinoids. The two most studied:
- Delta-9-THC -- CB1 partial agonist responsible for psychoactive effects (euphoria, altered perception, impaired memory, increased appetite)
- Cannabidiol (CBD) -- weak CB1/CB2 affinity; modulates 5-HT1A, TRPV1, GPR55; anti-inflammatory and anticonvulsant properties without psychoactivity
FDA-Approved Cannabinoid Drugs
- Dronabinol (synthetic THC) -- chemotherapy-induced nausea, AIDS-associated anorexia
- Nabilone (synthetic THC analog) -- chemotherapy-induced nausea
- Epidiolex (purified CBD) -- Lennox-Gastaut syndrome and Dravet syndrome (severe pediatric epilepsies)
Emerging Targets
FAAH inhibitors increase anandamide levels and are under investigation for anxiety and pain. MAGL inhibitors raise 2-AG. Allosteric CB1 modulators aim to fine-tune signaling without full receptor activation.
Key Takeaways
- Endocannabinoids are retrograde messengers that modulate presynaptic neurotransmitter release
- CB1 receptors in the CNS mediate the psychoactive and analgesic effects of cannabinoids
- CBD lacks psychoactivity but has anticonvulsant efficacy in severe childhood epilepsies
- Enzyme inhibitors (FAAH, MAGL) represent a next-generation approach to cannabinoid therapeutics