NMDA antagonists COMBINED WITH NMDA agonists causes headache?

[Ventrusii]

I love Dextromethorphan (Henceforth Dex) for its over-the-counter strong serotonergic effects, and also for its dissociative effects as well, but I rarely use low dose Dex for its NMDA Antagonist properties, as they're mind-numbing at best and stupefying at worst. Because of this, as well as wanting to keep my tolerance for NMDA receptors down so that when I use Dex for its NMDA antagonist properties, the receptor isn't already at a higher tolerance because of my low-dose uses.

I choose to use ~20-30mg Noopept (With a choline source to prevent hangover from this) and 1g glycine along with my low-dose Dex to attempt to keep my tolerance down. The Noopept to help modulate/agonize/do something positive... I don't remember exactly what it is to the NMDA receptor, only that it increases activity/effectiveness. I use the 1g glycine to agonize the NMDA receptors as well.

The only problem with this, is that when I do this, I ALWAYS get a headache. I sometimes also get migraines with or without aura, but I'm also prone to migraines outside of all of this, so It's not much of a surprise that I'm getting them. I get more migraines than regular headaches, to put it into perspective. I was wondering, because I never get headaches on Dex without agonizing the NMDA receptor, is it because of the fact that I'm taking an NMDA receptor agonist along with an antagonist that it causes wonky effects? I'm completely left clueless, so if anyone could help, that would be wonderful.

(P.S., I find that using this combo, taking 60mg Dex (as a 68kg teenage male, so slightly <1mg/kg) puts me in a wonderful, happy and sociable mood for hours, whereas without the NMDA agonizing combo 60mg gives me a slight... slight drunken feel with usually little but sometimes barely any mood lift. I'm so confused, but yet, so happy that this works. Anyone have an answer for why NMDA agonism causes a better mood or potentiates the SERT activity of Dex?)

 

[sekio]

DXM on its own is actually a poor NMDA antagonist, most of the NMDA blockade comes from its metabolite DXO, as I understand it. Functionally speaking it is a SNRI with 10x more affinity for serotonin than norepinephrine. Because it acts to increase norepinephrine/adrenaline release it can increase blood pressure and cause headaches under the right conditions. Maybe the Noopept just potentiates this aspect?

Also, oral glycine is not psychoactive - in vitro it acts as a NMDA agonist, sure, but so do a few other small amino acids. The problem with those are that your body uses them for protein synthesis and also they have limited transport into the brain. So if you eat glycine it will not increase concentrations in the brian enough to have any effect, unfortunately. The same goes with consuming other amino acids like L-DOPA, 5-HTP, glutamate etc - most of an oral dose ends up excreted or in peripheral blood circulation, not delivered to the brain.

The thing with mixing drugs that activate and drugs that block a certain receptor is quite simple, the one with the higher affinity will produce effects, usually. If you took a NMDA antagonist and then a NMDA agonist with higher affinity, you would simply reverse the dissociative effects, assuming there was no other secondary target of either drug. A headache likely comes from some interaction between the Noopept and the DXM... not necessarily attributable to the NMDA receptor either.

There could also be expectation/nocebo effects at work if you haven't tried a double blind experiment to rule those out.

 

[Ventrusii]

Ah. Thank you, sekio. I did look it up and found that Noopept does in fact increase blood pressure. Do you have any opinion on taking half a viagra to lower blood pressure to counteract the headache-inducing effects of DXM & Noopept? Would it even work in the brain or would it just work systemically?

Also, How would one take glycine then? Should I take it several hours after a high-protien meal, to reduce the need of the glycine for protien synthesis?

 

[sekio]

I don't think Viagra lowers systematic blood pressure very well, I was under the impression it was more selective for causing erections. PubMed suggests it causes a small but not clinically significant dropp in blood pressure, becoming stronger in older individuals and weaker in twentysomethings. [ref]

Personally I would go for a tall glass of water, an ibuprofen, or even just laying down for a nap in a quiet dark room, instead. Or THC if you can handle it. Reducing your Noopept consumption could also help and would be the most obvious way to get around this. If you are using low dose DXM I would actually not worry about using NMDA agonists for tolerance; the low-dose effects of DXM are mostly mediated by its SNRI behaviour as well as sigma-receptor agonism.

Re: glycine, If you consume any protein at all, you don't need to intake glycine whatsoever. It is literally the simplest amino acid, and as a result is quite abundant. In fact, I think your body can make glycine de novo if it needs to - it's not an essential amino acid. I'd save your money.

 

[Ventrusii]

Ah, thank you. The past several times ibuprofen has been my savior, and thank you for bringing light to the fact that glycine doesn't need to be supplememted.

 

[sekio]

Fun fact, gelatin contains a large fraction of glycine (and proline, hydroxyproline and a few others). So make a bowl of Jell-O or eat some Haribo gummies next time?

 

[Nagelfar]

The same goes with consuming other amino acids like L-DOPA, 5-HTP, glutamate etc - most of an oral dose ends up excreted or in peripheral blood circulation, not delivered to the brain.

Amino acids water soluble enough to, *ahem* skip first pass metabolism straight to the vascular system, or usable with an Intralipid type preparation? Would that then have any NMDAra effects?

Fun fact, gelatin contains a large fraction of glycine (and proline, hydroxyproline and a few others). ... eat some Haribo gummies next time?

...is that why I love eating those things..? ;-P