5-HT2A agonist
5-HT2A serotonin receptor agonist
- If BBB-crossing: ↑ cortical glutamate signaling → psychedelic effects
- Key receptor driving serotonin toxicity
- Tolerance to psychedelic effects develops within days via receptor downregulation
- ↓ DA release in nigrostriatal pathway
- SSRI-induced akathisia
- Implicated in SSRI sexual dysfunction (also 5-HT2C)
- Associated with rapid antidepressant effect (clinical trials)
- Altered emotional processing
- Promotes synaptic plasticity (preclinical data)
- Pupillary dilation
- Increased heart rate
Drugs with this mechanism (8)
- N,N-dimethyltryptamine — Short-acting serotonergic psychedelic; active principle of ayahuasca.
- Ergotamine — Ergot alkaloid for migraine; vasoconstrictive, largely supplanted by triptans.
- Lysergic acid diethylamide — Classic serotonergic psychedelic; potent 5-HT2A agonist.
- mCPP — Trazodone and nefazodone metabolite; 5-HT2C agonist causing anxiety and dysphoria; accumulates when CYP2D6 is inhibited.
- Methylenedioxymethamphetamine — Serotonin releaser (empathogen) under study for PTSD.
- Mescaline — Classic peyote psychedelic; a 5-HT2A agonist.
- Psilocin — The active dephosphorylated form of psilocybin; a 5-HT2A agonist.
- Serotonin — The endogenous ligand at fourteen receptor subtypes; the home of serotonicity — synaptic serotonin elevation.
Self-check
- Why can tolerance to psychedelic effects develop within days?
5-HT2A receptor downregulation. - What is the evidence level for 5-HT2A agonism promoting synaptic plasticity?
Preclinical data.
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