NMDA Receptor Antagonists: Slightly More Than You Wanted to Know
grillbert.substack.com25 points by surprisetalk 21 hours ago
25 points by surprisetalk 21 hours ago
It's important for casual readers to remember that clinical studies exist to prove whether theories work in real life, because there's still a lot of unknowns, and genetic variability between people.
Treatment for PCP is benzodiazepines/antipsychotics, not ketamine.
Phencyclidine became a reference molecule for many modern drugs currently used.
also in the real world clinical experiences.
Memantine, at least for Alzheimer's, is basically like giving the patient water, I've never actually seen it change anyone's life significantly.
There's also all the stuff w/ NMDA-receptor encephalitis, a lot of it was written up by Josep Dalmau
Author here,
Benzos aren't used in cases wherein the ER staff suspect the patient is at risk of respiratory depression. Ketamine is effective in these cases, that's the point I was making, I could rephrase it though.
I've been taking 90mg DXM with my 150mg Bupropion XR for the last few years.
Noticed a moderate improvement. I think NMDA is one of those targets that's flown under the radar, but now is being implicated with all sorts of cognitive processes.
It causes memory and thinking problems. Some people are less sensitive to it than others, but i think that's why they haven't caught on. People online definitely experiment with using dxm and the alzheimers drug memantine. From what I've heard they're just too strong. Not sure why something weaker and not functional has never been produced though
Isn't DXM a disassociative at high doses? Moreover, don't people risk getting quite addicted to it, escalating their dose beyond even what you take? Perhaps your dose is stable, but even optimistically, it is management, not a cure. A cure is more possible with lower doses of DXM before it becomes a hard dependence.
The bupropion (Wellbutrin) portion of the combination mentioned above serves as a CYP2D6 inhibitor as well, actually boosting the action of the DXM in the body. Auvelity dosing starts lower with just 45mg of DXM, jumping to 90mg as the tolerance curve starts to set in.
CYP2D6 metabolizes DXM into a much more potent NMDA antagonist (dextrorphan, sometimes abbreviated to DXO). Inhibiting it boosts some action(s) of DXM but likely reduces the NMDA antagonist effect.
This article is remarkable incomplete. Why is he only talking about the effect ion the NMDA receptor when ketamine effect much more than that and a lot of stuff we do not know. At higher doses it start effecting other receptors which is why a higher does has seemingly opposite effects.
You can see the K values for the receptors ketamine effects on wikipedia:
https://en.wikipedia.org/wiki/Ketamine#Pharmacology
He does not seem to know ketamine is a D2 receptor agonsit, the same as PCP, yet he mentions it for PCP!
Like most of the "nootropics" people I read they speak only in "vibes".
Author here,
>This article is remarkable incomplete
True! There's other posts in this vein on the blog. Most recent posts have concerned the NMDA Receptor, i'm mainly using ketamine to tease out intracellular effects of different NMDAR currents.
>At higher doses it start effecting other receptors which is why a higher does has seemingly opposite effects.
Also true, but not sure if that necessarily conflicts with what I'm writing about here in comparing Ketamine to Memantine.
>He does not seem to know ketamine is a D2 receptor agonsit, the same as PCP, yet he mentions it for PCP!
Learned this halfway through writing, forgot to amend that section. Completely on me.
Memantine + half-dose telmisartan (for up to 3 months max) is remarkably effective for treating depression, with no addiction and no withdrawal. One does have to scale up and scale down the doses gradually, and suffer the drowsiness and 10+ point BP reduction, but it works. Do not exceed 3 months because the dopaminergic effect of memantine will catch up by then, and you don't want psychosis from it. One must also avoid common triggers of depression, e.g. fast food, rancid oil, plastic packaging for hot foods, and air pollution from fires. It is also mandatory to engage in strenuous daily exercise, e.g. running, for this regimen to work, although exercise alone doesn't fix it. Of course, someone who hasn't tried it will find it easy to be critical and dismissive, but they're not the ones who need it, and their opinion doesn't matter. The beauty of this solution is that one you're treated, you're cured (assuming you stopped the environmental triggers). There are concrete logical pharmacological, neurological, and physiological reasons for this solution's effectiveness.
So you posted a wall of medical advice - surely you have links to the peer reviewed studies that back it all up, right?
As inappropriate as it may seem, it's also inappropriate for any adult responsible for themselves to make their own health decisions per some random online comment, whether true or not.
That's missing the point altogether. A basic investigation will yield:
* Memantine has NMDAr antagonism effects which will weaken depressive thoughts.
* Memantine has dopaminergic agonist activity (which builds very slowly), eventually improving mood.
* Telmisartan has PPAR gamma activation effects which synergizes with its ARB effect for potent neurological benefits.
* Intense exercise synergizes with all of the above, although it's less critical if the environmental trigger of depression is eliminated.
A reductive investigation will find that the individual components don't cure depression, and that's beside the point. It is only their combination that fully normalizes things.