Baseline Tone — The Brain's Own Cannabinoid Signaling
A quiet regulatory system runs constantly, tuning mood and memory.
- AEA, 2-AG: Main endocannabinoids (made on demand, not stored)
- Gi/o-GPCR: Receptor type (inhibits cAMP, opens K+ channels)
- Retrograde: Signaling direction (travels backward across synapse)
- 5–15%: Baseline occupancy (low tonic activation)
What the endocannabinoid system normally does
Regulates mood, appetite, memory, and pain in modest amounts.
Retrograde signaling at the synapse
Made postsynaptically, drifts backward, dampens further neurotransmitter release.
A feedback brake, not a constant broadcast signal.
From Lungs or Gut to Brain — THC's Journey Into the CNS
Highly lipophilic THC slips easily through the blood-brain barrier.
- 10–35%: Inhaled bioavailability (fast lung absorption)
- 4–12%: Edible bioavailability (first-pass liver metabolism)
- ~10 min: Inhaled peak time (rapid onset)
- 60–90 min: Edible peak time (delayed, unpredictable onset)
Why route of administration matters
Smoking peaks fast; edibles absorb slowly through the gut.
Crossing the blood-brain barrier
Lipid solubility lets THC pass the barrier almost freely.
Liver converts edible THC into a stronger active metabolite.
High-Affinity Binding Across Memory, Motor, and Reward Circuits
THC docks onto CB1 receptors dense in three key brain regions.
- Cerebellum: CB1 density peak (highest receptor concentration)
- Partial agonist: THC binding (weaker than full activation)
- 3: Key regions (hippocampus, cerebellum, mesolimbic)
- CB1 (CNS): Receptor family (vs CB1/CB2 peripheral)
Regional receptor density drives regional effects
Dense CB1 clusters explain memory, motor, and reward symptoms.
Partial agonist behavior
THC activates less efficiently than the body's own ligands.
Same receptor, different regions, different psychoactive symptoms.
Presynaptic Brakes — How CB1 Activation Changes Signaling
CB1 activation dials down release of several neurotransmitters at once.
- ↓ Glutamate: Hippocampus effect (impairs memory encoding)
- ↓ GABA/Glu: Cerebellum effect (alters motor timing)
- ↑ Dopamine: Mesolimbic effect (drives reward, euphoria)
- Gi/o coupling: Mechanism (presynaptic inhibition)
Presynaptic inhibition mechanism
CB1 suppresses calcium influx, reducing vesicle release upstream.
Region-specific transmitter changes
Memory circuits quiet down; reward circuits fire up dopamine.
One receptor, opposite effects depending on local circuitry.
The Classic High — Euphoria, Memory Gaps, and Altered Coordination
Dose and route together shape intensity, timing, and duration.
- Route-dependent: Peak subjective effect (minutes to hours)
- Impaired: Short-term memory (disrupted encoding, not recall)
- Altered: Motor coordination (cerebellar timing disruption)
- Receptor downregulation: Chronic use (tolerance over time)
The combined psychoactive profile
Euphoria, short-term memory lapses, and coordination changes together.
Dose, route, and duration
Edibles last longer; inhalation hits harder and faster.
Same receptor mechanism, highly variable subjective experience.