There has been a continuing thread in the psychedelic literature stating that “DMT acts as a natural endogenous agonist of the sigma-1 receptor” which references this paper from 2009.
Around the same time, my lab showed that DMT is ~100-fold more potent at the 5-HT2A receptor and that its effects in mice are blocked by genetic deletion of the 5-HT2A.
A recent paper animals were initially treated with a modest dose of DMT (1 mg/kg) but then were infused with 2 mg/kg/hr for 24 hr (49 mg DMT/kg total)—which is a rather heroic dosing regimen. The effects appear to be mediated at least in part by sigma1 receptors as a sigma1-preferring antagonist BD1063.
The authors suggest:
“DMT and other sigma-1 receptor agonists via their interaction with the vascular and immune systems have the potential to complement current insufficient poststroke therapy due to their neuroprotective, central, and peripheral anti-inflammatory and BBB-protective effects.”
This could be true, but why would one ever focus on DMT as it has very low affinity for the sigma1-receptor (1-5 uM vs nM potency at 2A)? To investigate this I examined the sigma1-receptor affinities for many psychedelic drugs and compared this with their transduction coefficients for activating 5-HT2A receptor at the Gq pathway using data from our recent paper in Neuron.
The point is that DMT could have this effect but at doses at least 100 fold higher than psychedelic doses
I don’t have much skin in the sigma game, but one curious SAR jumped out in our norpsilocin analog paper from last year (https://pubs.acs.org/doi/10.1021/acschemneuro.3c00610):
There seemed to be a neat 5-HT2A/sigma split across a few of the N-substitutions (at least in the initial PDSP affinity screens):
N-allyl → mostly selective for 5-HT2A with respect to sigma
N-cyclohexyl → flips to sigma (~100 nM), with respect to 5-HT2A (~800 nM); also not HTR active
N-benzyl → roughly balanced between 5-HT2A and sigma, 95 nM and 40 nM, respectively
I don’t have the appetite or bandwidth to dig deeper, but if anyone wants to test their various sigma enigma hypotheses here, I’m glad to share compounds.