Cannabinoid Pharmacology

## 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