Tolerance reset of ketamine (and possibly lyrica) using glycine, glutamate noopept, and phenylpiracetam + MOA of NMDAr agonism.

[Snövit-Rödvit]

TI;dr Could anyone share their experience with using the mentioned substances or NAC to help reverse tolerance, and let me know if the amino acids can be taken together to achieve upregulation of NMDAr

Hi! Long time lurker first-time poster.
I understand that time is the best for a tolerance reset, but I am looking for ways to potentially speed up the process. I don’t have perma tolerance but it is rather high. I’d also like to enjoy pregabs again which has no effect after heavy ket use even after 3 weeks of cessation, but my main focus is ket.

I've read that Noopept agonizes NMDAr, so l'm wondering if it could be used to upregulate/ resensitize NMDA.

While I don't have access to sarcosine, I have read that glycine is also an NMDA agonist and have seen some positive reports. As for glutamine, it is also an NMDA agonist, so I was thinking of taking them both at the same time or cycling them every other day. Or is NAC a better substance for my goal?

I am aware that when taken together, these amino acids can lead to protein synthesis, but I'm not sure if this means they lose their NMDA action.

Additionally, my friend swears of racetams having a positive effect on tolerance by upregulating NMDA. However, I am confused about this since racetams are AMPAkines. And I can’t try his because he’s stopped using ket and in turn racetams.

 

[Vastness]

Racetams are all NMDA agonists and if it was as simple as just upregulating/downregulating specific neurotransmitter systems then they'd probably be a good option. Sarcosine would be better, IIRC it's more selective and maybe there's some research that actually shows it does indeed upregulate NMDA, at the cost of it actually feeling kinda unpleasant in my experience when I was doing way too many dissos and didn't really enjoy not having a large chunk of my NMDA system muted as much as possible.

In general though the whole concept of "tolerance reset" is a myth, the brain is just too complicated and there aren't substances that are just 1:1 opposites of each other in terms of the neuronal changes they induce, so while you might have some success affecting the character of your tolerance, you will still be tolerant to the drug you've been taking too often. Just take a damn break, IMO/IM(extensive)E.

 

[Snövit-Rödvit]

Thank you for your answer! I know tolerance reset isn’t possible I worded it wrong, just thought I could help it along, still planning on taking a break. It’s strange Sarcosine is supposedly legal in my country but no vendors sell it here. I suppose it’s legal to import but not sell. Oh well I’ll probably skip it altogether.

But is lyrica cross-tolerant with ketamine? Some people say yes some say no. I have tolerance to it now but I don’t know for certain if it was the ketamine.

Racetams are all NMDA agonists and if it was as simple as just upregulating/downregulating specific neurotransmitter systems then they'd probably be a good option. Sarcosine would be better, IIRC it's more selective and maybe there's some research that actually shows it does indeed upregulate NMDA, at the cost of it actually feeling kinda unpleasant in my experience when I was doing way too many dissos and didn't really enjoy not having a large chunk of my NMDA system muted as much as possible.

In general though the whole concept of "tolerance reset" is a myth, the brain is just too complicated and there aren't substances that are just 1:1 opposites of each other in terms of the neuronal changes they induce, so while you might have some success affecting the character of your tolerance, you will still be tolerant to the drug you've been taking too often. Just take a damn break, IMO/IM(extensive)E.

 

[Vastness]

But is lyrica cross-tolerant with ketamine? Some people say yes some say no. I have tolerance to it now but I don’t know for certain if it was the ketamine.

No, it's not cross tolerant whatsoever, there is practically no overlap in mechanism of action or neurotransmitter systems affected. I have no idea why anyone would say that it is...

On sarcosine - I will say having now qualified that we aren't talking about a total tolerance "reset" that after I'd taken 6 months at least off from all dissos, I no longer found sarcosine so unpleasant. In another thread a while back about something similar I remember musing that maybe sarcosine could be a fairly brutal route back to some kind of normality if you've scrambled your brain with too many dissos and have the time, lack of any pressing need to not feel shit for a while, and mental fortitude to endure some degree of psychological sufferring for the sake of more rapidly reversing certain changes induced by dissos... then it might be a good option. It might also be a terrible idea but there's at least one poster here I remember who I considered to be fairly credible who did report success using sarcosine to feel better after doing too much K - maybe they even reported some tolerance reduction, in some form, I can't remember exactly. They did take a lower dose than is sometimes advised, I think, or at least than when I tried it, like 500mg / day or / dose compared to the 2g ish I'd take at once. But again in my experience it is a fairly brutal reversal, of you're using too much K it's usually coz you've come to like having your NMDA system heavily inhibited - won't judge the reason, in my case definitely to avoid healthy emotional processing but whatever the reason - so then taking something that turns all the NMDA-lights back on suddenly can be just too much and profoundly unsettling... YMMV of course, but I guess this all points to SOMETHING going on in line with your objectives, even if there's not enough information anywhere to know if it's actually a good idea or not in the long run.

 

[Snövit-Rödvit]

Some people on a Swedish drug forum mentioned the possibility of cross-tolerance. Initially, I was unsure about this because pregabalin is a VGCC drug. However, after doing more research, I found out that it indirectly blocks NMDAr. This made me consider the chance of some level of cross-tolerance and led me to ask about it. It seems that my tolerance to pregabalin is higher than I had thought. Thank you for clearing that up.

I've decided to avoid sarcosine, glycine, and, glutamate. I'm considering ordering phenylpiracetam and noopept for stimulant enhancement. Once again, I really appreciate such a detailed answer.

 

[Snövit-Rödvit]

No, it's not cross tolerant whatsoever, there is practically no overlap in mechanism of action or neurotransmitter systems affected. I have no idea why anyone would say that it is...

On sarcosine - I will say having now qualified that we aren't talking about a total tolerance "reset" that after I'd taken 6 months at least off from all dissos, I no longer found sarcosine so unpleasant. In another thread a while back about something similar I remember musing that maybe sarcosine could be a fairly brutal route back to some kind of normality if you've scrambled your brain with too many dissos and have the time, lack of any pressing need to not feel shit for a while, and mental fortitude to endure some degree of psychological sufferring for the sake of more rapidly reversing certain changes induced by dissos... then it might be a good option. It might also be a terrible idea but there's at least one poster here I remember who I considered to be fairly credible who did report success using sarcosine to feel better after doing too much K - maybe they even reported some tolerance reduction, in some form, I can't remember exactly. They did take a lower dose than is sometimes advised, I think, or at least than when I tried it, like 500mg / day or / dose compared to the 2g ish I'd take at once. But again in my experience it is a fairly brutal reversal, of you're using too much K it's usually coz you've come to like having your NMDA system heavily inhibited - won't judge the reason, in my case definitely to avoid healthy emotional processing but whatever the reason - so then taking something that turns all the NMDA-lights back on suddenly can be just too much and profoundly unsettling... YMMV of course, but I guess this all points to SOMETHING going on in line with your objectives, even if there's not enough information anywhere to know if it's actually a good idea or not in the long run.

I hope the rest of your day or evening goes well. I truly appreciate all your help.

 

[someguyontheinternet]

What is the evidence that ketamine tolerance is caused by NMDAR downregulation?

 

[Vastness]

I think it would be upregulation in fact, maybe I mixed up those terms because I admit I do find it a little confusing. I don't know if there's something more complex I'm overlooking - no doubt there are many factors at play, of course - but in essence that's usually how tolerance works for any neurotransmitter system. Ketamine is an NMDA-inhibitor, and in simple terms blocks access to those receptors for the endogenous neurotransmitters that would usually bind to them. So in order to maintain homeostasis the brain responds by creating more NMDA receptors, so it's harder for the same amount of ketamine to interfere with normal neurochemical function because there are now more receptors for your endogenous NTs to bind to - ergo, tolerance... pretty sure that's how it works anyway.

 

[someguyontheinternet]

There are other methods of tolerance as well including changes in metabolism to clear the drug faster or changes in drug transport pumps to prevent uptake. Changes in astrocytes to modify how well things cross the BBB. The NMDAR is made up of 4 subunits which always contains NR1 and some combination of various NR2 or 3 subunits. Iirc ketamine specifically binds the B subunit so if B subunits get swapped out for a different one, say A C or D (I don't remember off hand which has similar properties to B, I think its A that is most similar for conductance and kinetics), then you get less ketamine binding. There may even be changes in AMPAR or kainate receptor membrane insertion or subunits which can provide the extra conductance at the glutamatergic synapse. I don't think we can say we know for sure the mechanism of tolerance until there are some published studies on it, although I have not personally looked.

 

[Vastness]

Hmm yeah, I mean as I say I don't think it's as simple as upregulation of NMDAR only but it seems like it makes intuitive sense that it would be a fairly significant factor, beyond that though I'll admit I don't really have a clue. There is this study - https://pubmed.ncbi.nlm.nih.gov/23065140/ - which concludes:

These findings suggest that prolonged ketamine exposure produces an increase in NMDA receptor expression (compensatory upregulation), which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to elevated ROS generation and neuronal cell death.

Granted, it's an animal study, and I believe it's been shown elsewhere that the actual cell death thing can be a risk in human infants but has not really been definitively demonstrated in adults (although - IMHO - ketamine likely is at least "lightly" neurotoxic even in adults, given sufficient dose and/or frequency of dosing - neurotoxicity has been shown in adults when other drugs are involved, primarily stimulants, although of course it's hard to separate out individual substance effects in these kind of observational studies of polydrug users).