Category: receptor_pharmacology
The 5-HT2A receptor is a Gq-coupled GPCR expressed at high density on cortical layer V pyramidal neurons (especially prefrontal cortex) and is the obligate target of classical psychedelics — psilocin (active metabolite of psilocybin), LSD, DMT, mescaline, 5-MeO-DMT. Pharmacology distinguishes psychedelic from non-psychedelic 5-HT2A agonists: biased agonism for β-arrestin-2 + specific G-protein subtypes (Gq, but with downstream signaling that engages BDNF/mTOR — see [[bdnf_trkb_neurotrophic]]); recent evidence that psilocin + LSD bind TrkB directly (Moliner 2023) and that head-twitch response in rodents (a 5-HT2A psychedelic-specific behavior) tracks subjective "trip" intensity in humans. Functional mechanism: 5-HT2A → Gq → PLC → IP3 + DAG → Ca²⁺ + PKC → cortical pyramidal cell depolarization → glutamate release (especially on thalamic relay) → mGluR2/3 cross-talk modulates the experience (ketanserin blocks the experience; mGluR2 agonists dampen it). Persistent post-acute effects: ↑synaptogenesis in PFC (rapid, mTOR-dependent), ↑plasticity, ↓DMN connectivity (network "reset" hypothesis for depression/anxiety/addiction). 5-HT2A is also a major off-target for atypical antipsychotics (high 5-HT2A:D2 ratio defines "atypicality" per Meltzer hypothesis — clozapine, olanzapine, risperidone, quetiapine block 5-HT2A → ↓EPS, ↑metabolic effects). Pure 5-HT2A inverse agonists: pimavanserin (Parkinson disease psychosis — no D2 blockade); historic ritanserin (depression trials, failed). Therapeutics — psychedelic: psilocybin (COMP360 in TRD phase 3); MDMA (PTSD — Lykos); LSD trials. Anti-psychotic: pimavanserin selective; nuplazid. Cross-links: [[serotonin_receptor_pharmacology]] (parent), [[bdnf_trkb_neurotrophic]] (downstream psychoplastogen mechanism), [[mglur_metabotropic_glutamate]] (mGluR2/3 modulation of psychedelic).