3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.2.10 Cannabinoids
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Written by Resident Doctor Committee · Published
Endocannabinoid signalling
Endocannabinoids are retrograde messengers: the postsynaptic cell makes them, and they reduce transmitter release from the presynaptic terminal.
Anandamide and 2-arachidonoylglycerol (2-AG) are lipids made on demand, not stored in vesicles.
Fatty acid amide hydrolase (FAAH) breaks down anandamide, and monoacylglycerol lipase breaks down 2-AG.
CB1 and CB2 receptors
Both receptors couple to Gi/o proteins.
Feature | CB1 | CB2 |
|---|---|---|
Main site | Brain, on presynaptic terminals | Immune and peripheral cells |
Brain expression | Dominant | Low levels only, mainly microglia |
Effect of activation | Reduced transmitter release | Immune and inflammatory modulation |
CB1 density is high in the basal ganglia output nuclei (including the substantia nigra), cerebellum, hippocampus, cortex and amygdala.
CB1 density is low in the medullary respiratory and cardiovascular centres of the lower brainstem, which explains why cannabis has low lethality.
Cannabinoids in use
Compound | Action | Clinical point |
|---|---|---|
Tetrahydrocannabinol (THC) | Partial agonist at CB1 and CB2 | Can cause transient psychotic-like symptoms |
Synthetic cannabinoids | Potent full CB1 agonists | Severe agitation, seizures, cardiovascular injury, psychosis |
Cannabidiol (CBD) | Low CB1 affinity, no typical intoxication | Prescribed for Dravet, Lennox-Gastaut and tuberous sclerosis epilepsies |
THC accumulates in fat, so urine stays positive for weeks after regular use, which shows exposure rather than current impairment.
Withdrawal
Repeated use desensitises and down-regulates CB1. Withdrawal begins within 1 to 3 days, peaks in the first week and brings irritability, anxiety, insomnia, vivid dreams and appetite loss.