NMDA antagonists have been losing their magic

[donD]

Hi all,

I've been on adderall and vyvanse for the past year. At first, nmda antagonists along with dopamine precursor supplements solved my tolerance issues. However, now it seems as though I'm tolerant to the nmda antagonists themselves. 60mg of DXM softgels would instantly make me feel the amphetamine again. Now, even with doses of 120 mg, it seems like i cant get it to work. Anyone have any answers or run into this problem themselves? Thanks.

 

[AlphaMethylPhenyl]

Don't think this is that advanced.

Anyways, stimulant tolerance is a tricky beast. It never goes away completely, as in, you'll never feel the same way you did after the first few doses. That's a good thing in my opinion, though, because it reduces the abuse and addiction potential. That's one of the reasons they're used. They're not supposed to produce euphoria, only a mood lift in severe treatment resistant depression (if it works). For ADHD they're simply supposed to produce focus, and for narcolepsy they just keep people from falling asleep throughout the day.

I would recommend not taking tyrosine or dopamine precursors. They mess with the internal balance of amines in the brain.

NMDA antagonists can't prevent tolerance, even if you take them regularly. They only prevent tolerance from developing as fast.

Taking even 60mg of DXM daily probably isn't a good idea in my opinion. 120mg is a lot, too.

 

[N0 W4RN1NG]

Ho-Chi-Minh, good advice, but 60mg daily DXM is fine. 120mg is too much though.

OP DEFINITELY avoid Tyrosine. As a daily supplement at least. That will actually cause pretty quick downregulation of dopaminergic neurons in conjunction with DA releasers like amphetamine - meaning after the first few days, your tolerance will be a lot worse.

OP: You should take breaks from the 60mg DXM on the weekends though, and you also should not take amphetamine EVERY DAY. You need at least 1 day off each week, preferably 2-3, or you can guarantee your tolerance will be slowly going up whether you take 1000 supplements or not.

 

[drancer]

Oh, but taking tyrosine after an amp binge definitely smooths out the comedown.. at least for me! So should the tyrosine be taken for just up to 3 days after the binge, and then gradually cycle that off the daily supplement stack?

 

[N0 W4RN1NG]

^ Definitely - I would honestly try to just use it post-comedown once or twice.

L-tyrosine, N-acetyl tyrosine and L-DOPA (but interestingly, not DL-phenylalanine) have all been shown to markedly downregulate DA receptors in combination with amphetamine when given chronically.

 

[adder]

(removed incorrect information)

Have you ever taken DXM recreationally on its own in higher doses? I tried using 30-60mg of DXM a day to help me with benzodiazepine withdrawal set-back and to decrease my tolerance to Suboxone, so I can get off quickly. I noticed that on the second or third day I didn't need a dose at all, because the effect was still there (I was able to reduce my Suboxone dose from 8-12mg a day to 4mg right away and my pupils seem to be even more constricted). On the third or fourth day I only took 15mg and I think that I'm going to need 30mg at most to prolong the effect. Also, I'm planning to take a weekly break to avoid downregulation, even though my dose is like a therapeutic dose for cough. I used to be quite sensitive to DXM in the past though.

I think that you will be better off taking 30-60mg (or even 30-45mg) of DXM for a couple of days and then making a break even twice as long. With such a trick you may get better results. Also, be careful mixing amphetamine and DXM, try not to take them at the same time, after taking DXM I would wait at least 6 hours before taking amphetamine. Both drugs can be hard on your heart.

 

[endotropic]

NMDA antagonists downregulate NMDA receptors in the long run. That means your body lowers the quantity of NMDA receptors as a response to DXO. So in the end there are less channels that it could block and you're losing that "antitolerance" effect.

Wow that's really odd, sort of how some 5-HT2A antagonists will downregulate that receptor? It's really puzzling to me when the body seems to work against homeostasis like in these cases. Do you know where I can read more about that process?

 

[adder]

I was sure that there's evidence for this, but I've just realized that it must have been based on my impression or someone else's theory. It seems that they actually cause upregulation - article - but then again this is about PCP. It is a way more potent antagonist than ketamine or dextrorphan, and ketamine seems to cause neurotoxicity too in high enough doses. It's a good thing that you replied to my post and it didn't end up staying there for years with incorrect information.

NMDA receptors are voltage-dependent ion channels and their activation is a more complex process than activation of GPCRs (like those two aforementioned 5-HT receptors) involving inhibitory glycine binding to its site apart from glutamate or NMDA. Beneficial effects of dissociatives in depression are a result of a process that is also more complex than just plain NMDA channel blockade. Now I'm wondering if using low doses of DXM to help me with cloudy mind caused by benzodiazepine withdrawal could actually cause a rebound effect. I guess I need to revise my knowledge on NMDA receptors.

I've found one article saying that there are two distinct forms of NMDA receptors desensitisation, but only one form caused by agonists is discussed. Does anyone know what the second form of desentisation is?

 

[endotropic]

\
I've found one article saying that there are two distinct forms of NMDA receptors desensitisation, but only one form caused by agonists is discussed. Does anyone know what the second form of desentisation is?

One form results from a weakening of agonist affinity when channels are activated whereas the other form of desensitization results when channels enter a long-lived nonconducting state.

Basically they're saying that agonists desensitize the receptor in two different ways - 1) by reducing their own affinity 2) by driving the receptor towards a non-conducting state even in the agonist bound state.