Comment · Fri, December 2, 2016 · Ceretropic & Nootropics Depot
What causes DXM's afterglow effect?
Original post in this thread
baccheion · 6 points
Serotonin? Opioid receptors interactions? Upregulation after NMDA antagonism? Something else?
Maybe there'll be some combination of supplements I can take to mimic/recreate this effect.
What they were answering
hootnoot · 1 points
Thanks for the studies! I like the NMDA DA release one especially.
Do you know anything else that elicits an NMDA mediated DA enhancement? I know of Ketamine(and other arylcyclohexylamines) and Nitrous, maybe Alcohol(at higher doses).
I don't get it, though. I've never had much benefit from Sig1, whether it's an additional target to an SSRI or coupled with an MAOI. With DXM, Sig1 might be responsible for it, but Ketamine, which has a similar ish mechanism but tighter binding with NMDA(compared to DXM) and lower binding of Sig1(With DXO it's in nM vs uM in Ketamine) exhibits a more potent and robust AD effect at a FRACTION of the dose. Lower doses would hardly touch Sig1. None of the metabolites touch Sig1 either from a quick search. It does a lot of things though, involving MTOR, GSK-3 and so on, so I can't say. All I know is it shares some commonalities with other NMDA antagonists that have similar AD effects. And that DXM is pretty understudied in this regard, as are similar things like MXE.
It might be the mechanism for lower doses like you mentioned here though:
https://www.reddit.com/r/Nootropics/comments/2tbyma/low_dose_dxm_as_a_nootropic/
Can you expand on that? I'm going to do that myself soon - would love to hear from you about it.
I tagged you in a comment about DXM/DXO a few days ago and to hear your inputs but I appreciate you're probably busy and missed i…
u/MisterYouAreSoDumb · Ceretropic & Nootropics Depot
Dizocilpine: The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice
Rhynchophylline, which is found in kratom, lowered DA in some brain regions, but caused its release in others: Effects of rhynchophylline on motor activity of mice and serotonin and dopamine in rat brain.
Dexanabinol, a synthetic cannabinoid derivative that is devoid of direct CB receptor affinities, potentiates dopamine release: Interaction of Dexanabinol \(HU-211\), a novel NMDA receptor antagonist, with the dopaminergic system
The sigma-1, NMDA, AMPA, CB, and GABA systems are all much more linked than many people think. It's easy to fall into the idea that these systems are independent of each other, but we still do not fully understand all the specific interactions between them. Just look at things like GLYX-13 and NRX-1074. They are partial agonists at the gycine site of the NMDAR, and lead to similar antidepressant effects as ketamine WITHOUT increases in DA or psychostimulatory actions.
Take a look at this paper: NMDA antagonists under investigation for the treatment of major depressive disorder
New insights into the understanding of the role of the mTOR pathway in the mechanism of depression treatment might come from research conducted by Workman et al. who showed that the mTOR-dependent antidepressant-like activity of Ro-6325 requires GABA B receptor signaling [40] . In light of these findings, it is quite surprising that there are recent studies indicating that in the hippocampal synaptosomes, a single dose of ketamine can reduce glutamate release from presynaptic terminals by impairing accumulation of SNARE complexes. Attenuated glutamate release may be a consequence of dephosphorylation of a-calcium/calmodulin- dependent protein kinase II (a-CaMKII), decreased level of synaptic vesicle protein synaptogamin 1, and a concomitant increased protein level of synapsin1 [41] . Similar modifications in the SNARE complex formation are also observed after chronic treatment with classic antidepressants [42,43] . However, it remains an open question whether these presynaptic effects have significant importance for ketamine’s antidepressant- like activity after acute treatment. In addition, it is worthy to mention that antidepressant activity of selective GluN2B antagonists may be associated with the downstream pathways of sigma-1 receptors. Therefore, co-treatment of NMDA selective antagonists with sigma-1 receptors ligands may be a chance for new antidepressant therapeutic solutions [44-46] .
That paper is a fantastic read, and really digs into the specifics behind the complex interactions between some of the systems.
Can you expand on that? I'm going to do that myself soon - would love to hear from you about it.
What do you want me to expand on? I actually just finished a cycle of DXM yesterday.