I remain interested in amanita's actual pharmacological properties: it used to be conventional wisdom that it was primarily a GABA agonist with some NMDA antagonism as well, but I remember reading that it's NMDA effects are now considered unlikely to significantly contribute to the experience. GABA agonists aren't exactly hallucinogenic, though--although the Z-drugs do come to mind... Hmm.
That leaves it with... Just NMDA antagonism, which many people find magical but I find to generally be rather humdrum. Still: it's an unusual property in the plant world, as far as I can tell, shared only with unrefined opium off the top of my head (though minus the opioidergic effects).
Now, this could be complicated by the way it binds to GABA--maybe with some sub-type-specific reverse agonism modulating AMPA receptor expression in interesting ways, along the same lines that fasoracetam modulates GABA receptor expression In what is most likely an AMPA-mediated fashion.
Edit: just looked into it: muscimol binds as a direct GABA-like ligand, rather than a PAM, and binds not only to GABA-A but also as a partial agonist to GABAAρ. GABAAρ is a weird receptor that generally occurs as a homopentameric arrangement of rings of the 3 ρ-subunit variants around an ion pore. It is also actually *the most prevalent GABA subtype receptor in the retina*, although it's found elsewhere in the CNS as well, and differs by its slow induction time and sustained action through gated chloride channels. It's also a receptor that GABA itself has 10x more affinity for than GABA-A and yet benzodiazepines, barbiturates, and other GABA modulators aren't believed to interact with it. Given its activity as a direct ligand rather than as a PAM, we'd expect to see variable results depending on where and how it's displacing GABA--if it binds to GABA-Aρ with a high affinity but dissociates rapidly, for example, this might have the end result of increasing neuronal activity in some brain regions, where it might be doing a poorer job than endogenous GABA at evoking the slow-moving GABAAρ receptors. Conversely, it could be doing the opposite effect--but in the process activating pathways that we don't normally associate with GABA only because most GABAergics don't interact with this receptor type--like... for example... activity in the retina. I'm also thinking of the kind of cortical activity that goes on during sober relaxation--day dreaming? Imagining, remembering, wishing?
Some people are really fond of the Z-drugs. They make me too tired to stay awake for the weirdness to kick in... But this does make me wonder whether they've ever been checked for GABAρ affinity... Though as PAMs binding in a totally different way than GABA, at a pocket formed across residues on the α and γ subunits of the receptor complex, and belonging to a bulkier structural class... I'm leaning towards probably not--at least not directly.
Still, zolpidem binds selectively to α1-subunit-containing receptors, and doesn't show activity at α1γ1 or α1γ3 containing receptors.... and γ2-containing receptors have been shown to form oligoheteromeric interactions with GABAAρ receptor complexes... So Zolpidem binds relatively selectively but with a very high affinity to α1γ2-containing receptors, some of which are paired with GABAAρ. I think we've found ourselves a shared mechanism, and also a very unconventional receptor target for hallucinogenic effects. I wonder what it would be like with the "conventional" GABAA affinity stripped out... Or if that would even be safe. Muscimol's GABAA affinity may be all that stands in the way of potential neurotoxicity, considering that it directly competes with endogenous GABA at the GABA-binding site of a membrane-hyper polarizing chloride channel.
)
