Comment · Thu, April 18, 2013
Why does psychedelic-induced glutamate release not cause excitotoxicity?
Original post in this thread
AtomikPi · 14 points
It's my understanding that serotonergic psychedelics cause glutamate release. More broadly, there was a very cool fMRI study showing that psychedelics disable certain "filtering" regions of the brain - very much in line with Huxley's argument in The Doors of Perception.
Now obviously it's well-established that psychedelics don't cause degeneration of cognitive abilities. I'm thinking of a study from the early 70s showing no loss of cognitive abilities in individuals who'd used LSD an average of 50 or so times.
So why, from a neurological perspective does the glutamate release not cause excitotoxicity? Is the magnitude not large enough? The brain repairs itself?
Please note I've googled this and not come up with any conclusive result. There is a thread saying "it doesn't" / "not large enough of an effect" but no actual explanation or substantiation of that claim.
What they were answering
AtomikPi · 2 points
Thanks for that response. And thanks to Cannibalsnail as well.
NMDA antagonist neurotoxicity is mediated by an indirect mechanism involving disturbances in multiple transmitter receptor systems subserving a complex neural network in which major excitatory pathways are ordinarily held under inhibitory restraint by glutamate acting tonically at NMDA receptors on inhibitory (GABAergic or noradrenergic) neurons. Blockade of these NMDA receptors inactivates the inhibitory mechanism thereby disinhibiting the excitatory pathways, and unleashing excitotoxic activity that serves as the proximal cause of neuronal injury. Given evidence for serotonergic innervation of GABAergic interneurons via 5HT2A receptors (Mengod et al. 1990; Sheldon and Aghajanian 1990; Cornea-Hebert et al. 1996; Mathews et al. 1996; Shen and Andrade 1996), we postulate that a 5HT2A receptor is located on one or more of the GABAergic neurons in the NRH neurotoxicity circuit, and that activation of this receptor by the 5HT2A agonist restores inhibition to the network and prevents neuronal injury.
And now for a largely unrelated question: in the study you linked, it suggests that "hallucinogenic" effects of psychedelics are mediated by the 5-HT2c receptor. In that case, do you know if the 2a receptor is thought to play any role in the subjective effects of psychedelics?
u/MisterYouAreSoDumb
Ohh sure, 5-HT2A is the primary site for psychedelic effects. This is why antipsychotics are antagonists of the 5-HT2A receptor.
5-HT2C should be more of a mood regulating site.