NMDA antagonists for tolerance, a collection of the evidence and anecdotal reports

[crOOk]

Actually, I used to use 2nd and 3rd plateau doses of DXM daily for the better part of a year, crOOk, and I never got a tolerance.

Ketamine I got a tolerance to and its permanent because of how much I did my first time... I've only done it three times but because I did like 200mg my first time with it, I have to do that much every time or I don't k-hole. At least that's the way it seems.

200mg is a regular breakthrough dose for a first timer. Mine was at 250mg back then and it was no overkill (160lbs, male, dried pharmaceutical racemic K applied intranasally).
Ketamine tolerance is weird though, the experience changes in quality even after long intervals of abstinence. I recently had a magical experience again after 3 months of ketamine abstention. From what I know ketamine tolerance (quantitative) can sky rocket to infinity. as in people doing several grams per day and be completely functional.

I'm just afraid that long term use of these nmda antagonists might lead to an even quicker developement of tolerance towards various substances. That'd really be a shame.

Come to think of it... My cannabis tolerance has been decreasing steadily throughout the years (been using for >11yrs). I use daily at ~.1g these days.

I've noticed this process started when I started using Ketamine 6yrs ago. Several times per week at first, occasionally for the past 4yrs. Later episodes of DXM use at lower dosages (60-200mg) for the antidepressant effect. ~5years ago a 4 month pcp binge of daily use.

I've always stayed relatively sensitive to booze which I am and have been very happy about.
I've always stayed sensitive to all empathogenic drugs unlike everybody else I've come to know who's done em more than a couple of times... I've rolled less than 50times I'd say, it's still absolutely overwhelming each and every time!

While psychedelics never manage to crush me anymore due to my very frequent former use, there have occured some massive changes in trip quality over the years which seemed to increase constantly along with a quantitative tolerance which rendered the whole class of substances utterly useless. Massive physical side effects, harsh comedown, hangover, the magic is gone. Since this tendency was pretty constant, NMDA antagonists seem to have brought no benefits to me in this respect. I still love DMT and Mescaline though which had never seen changes as grave as those with other psychedelics, though they still occured.

Interestingly, I seem to be extremely sensitive to SSRI's, namely citalopram which gave me some of the typical psychedelic side effects (yawning, feeling in my throat) and massive euphoria. I can already feel emotional changes at a threshold dose of ~1mg. Standard initial dose for citalopram is 10mg...

Sooo, considering I've done DXM and Ketamine fairly regularly, but not very frequently over the past few years, I could very well imagine that even this infrequent use has been having an effect on my sensitivity towards cannabis (sensitivity started increasing around the time I started using NMDA antagonists), alcohol, maybe even MDMA and also might have increased my sensitivity to ssri's compared to my (unknown) innate sensitivity.


Is it known whether the NMDA antagonists in question will only reverse tolerance and thereby increase sensitivity to the level that could be seen before the receptors had been pharmaceutically stimulated OR will it actually increase sensitivity by separate mechanisms, therefore allowing an increased sensitivity past "natural" levels?? Damn I still haven't read through those publications...

For my internal medicine rotation, I wrote a paper on NMDA receptor antagonism in the treatment of chronic pain. It seems that these drugs are a sort of 'reset button' on neural memory; tolerance to drugs, chronic pain, and negative thought loops are all forms of reinforced neural pathways. The reinforcement comes from the neurons inserting more NMDA receptors (actually ion channels) in the cell membrane, so that they can depolarize and fire more easily. Jamming these ion channels brings the cells back to their original firing threshold.

I think the clinical use of DXM and ketamine (to say nothing of any PCP analogs!) will always be controversial, because people not ready for an all-out mystical experience (that's most people), tend to find them highly frightening in psychoactive doses. Memantine, however, is a gem -- it's highly specific to the NMDA receptor, unlike the others just mentioned. I think it has great potential for treating a number of psychiatric and psychosomatic illnesses which are a result of reinforcing the wrong neural pathways over time.

I love theanine, too. 200mg of that, and I feel like a million dollars. I'd recommend anyone with minor depression, anxiety, or anger management issues start taking it.

Couldn't have said it any better!!

I'll assume you consume the theanine orally. Do you have pills, powder or just plain tea? Seems like green tea can contain up to 2500mg per 100g tea, that's about 250mg per cup.

 

[Dr. Beat]

I took Memantine for about 1.5 years while taking Suboxone to keep my tolerance down, which it did a lot. I would get on the nod some days on this combination, usually a few days after taking the Memantine.

My experience with Memantine is less is better! So I would only take it once a week, and only 5 or 10mg. And that was enough to make a big difference to my tolerance.

The side effects were very strong respirtory depression from both drugs together, so I got a lot of sleep apnea from these 2 drugs combined. To reduce the sleep apnea, I would have a cup of black tea just before bed, and no caffeine through the day so it worked maximum while sleeping.

Little to no high from cigarettes (was only an occasional casual smoker before) or alcohol, so I stopped drinking and smoking on this combination.

I also find Memantine reduces the positive effect of caffeine, and there are a few articles on Science Direct saying Glutamate is important for the caffeine high.

I think Memantine is the safest of the NMDA antagonists for human consumption after every I have read and tried.

 

[chaos_destroy]

Sorry if i missed it somewhere in this thread but is this tolerance reversal likely to be permanent? Or will it come back when the Memantine is stopped? Will doing this cause a tolerance to ketamine at recreational doses?

 

[crOOk]

Sorry if i missed it somewhere in this thread but is this tolerance reversal likely to be permanent? Or will it come back when the Memantine is stopped? Will doing this cause a tolerance to ketamine at recreational doses?

The latter question seems to be of relevance for our community. :D I have no idea about cross tolerance between ketamine and the nmda antagonists mentioned in this thread to be honest, but maybe someone else can enlighten us.
Regarding the permanence. I doubt it's permanent, but the effect does seem to last way past the point of drug excretion. We have the following anecdotal evidence for that:

-Dr. Beat's report of him only taking the Memantine once per week
-The fact that the antidepressant effects of some NMDA antagonists last way past the point of the actual intoxication, 1-2wks seems to be most common
-My experience of decreased cannabis tolerance throughout the years during occasional nmda antagonist use (see my long post 3 posts further up in this thread, frequency ranging from several times per week to a month without)

IF the mechanism MyDoorsAreOpen suggested (temporarily blocked nmda receptors) is what this is all about, then I couldn't imagine the effect to be permanent though. My cannabis tolerance does seem to increase slightly after not taking any nmda antagonists for a few weeks, but it's still way below what it used to be or what it is for most other cannabis users.

 

[MyDoorsAreOpen]

^ I never said the jamming of NMDA receptors, a.k.a. ancillary Ca++/Na+/K+ pores, was temporary. There are actually a number of physiological ways these pores can get clogged, with likely varying degrees of reversibility. I'm not well read enough on this to know whether the clogged NMDA receptors ever get endocytosed (drawn into the cell for disposal, 'taken out of circulation'), or whether it's just a matter of them staying in the cell membrane and remaining damaged and nonfunctional, but the effects of even just one use of a high-affinity antagonist seem to be quite long lasting.

I wonder if it's something akin to wiping your Etch-a-sketch™ or your hard disk, or the burn-in patterns on old TVs and monitors: for most intents and purposes you clear a whole lot of new space to establish new learned patterns of neural firing. But trace elements of the old pathways remain and are detectable on close scrutiny, and can become reestablished over time more easily than brand new ones can be formed.

NMDA receptor antagonists are no magic bullet. They have to be combined with effortful lifestyle modifications to have a permanent transformative effect. But they're the next best thing to a magic bullet.

 

[crOOk]

^ I never said the jamming of NMDA receptors, a.k.a. ancillary Ca++/Na+/K+ pores, was temporary. There are actually a number of physiological ways these pores can get clogged, with likely varying degrees of reversibility. I'm not well read enough on this to know whether the clogged NMDA receptors ever get endocytosed (drawn into the cell for disposal, 'taken out of circulation'), or whether it's just a matter of them staying in the cell membrane and remaining damaged and nonfunctional, but the effects of even just one use of a high-affinity antagonist seem to be quite long lasting.

I wonder if it's something akin to wiping your Etch-a-sketch™ or your hard disk, or the burn-in patterns on old TVs and monitors: for most intents and purposes you clear a whole lot of new space to establish new learned patterns of neural firing. But trace elements of the old pathways remain and are detectable on close scrutiny, and can become reestablished over time more easily than brand new ones can be formed.

NMDA receptor antagonists are no magic bullet. They have to be combined with effortful lifestyle modifications to have a permanent transformative effect. But they're the next best thing to a magic bullet.

Thanks for clearing that up! Even with the limited biochem knowledge you possess (more than I know about the subject) you manage, in simple words, to give me a new idea of a process that's been challenging me to see through it for quite some time.

The question would be though, by establishing new behavioural patterns while on a long term nmda antagonist schedule, wouldn't those new pathways get clogged pretty quickly as well? (just a rethorical question really... :D)
And also, what happens when tolerance has been decreased to a certain degree and the nmda antagonist is withdrawn (along with the other substance of [ab]use). Will their be a rebound in tolerance to (endogenous) transmitters binding to the receptors in question?

I'll probably know soon enough. :D

I'm still very curious about that theanine thing. I was close to buying a ton of green tea today. :D

 

[seep]

Okay so... Memantine restores the "magic" BIG TIME... I'm so fucked up right now and it feels incredible!

I'm totally getting similar results from Huperazine A. I've been taking 100 mcg twice daily for 4 days. I wonder if anyone else can relate to this w/r/t huperazine.

In case it's of interest to you, I've cut my alprazolam consumption in half. Not because I'm trying to give it up but because it's suddenly too potent. FWIW I have a 6-year daily alprazolam habit.

 

[MeDieViL]

Went to 40mg today. I just took 131.4mg of moon rocks and I'm coming up fucking HARD! Memantine's effect on tolerance is NO JOKE! HOLY SHIT!

I love this stuff! It has a DXM-like brain fog at first but that goes away and I actually think clearer with it than without it AND it prevented any withdrawal symptoms from such an abrupt drop in dose (25% of a benzo dose is a LOT to not have any withdrawals from - previously, a 5% cut would have me in withdrawals by the third day) then you get the added benefit of drugs actually working again! I'm already rushing and I only took the moon rocks like 15 minutes ago. This is insane! I took 150mg last weekend and didn't feel hardly shit for rushes even at the peak and I'm just COMING UP!

I memantine. Seriously. Amazing drug.

Hahaha, memantine is dramatically underrated, thx for posting your experience, its amazing stuff!

As for tolerance to memantine itself, this does not appear to be the case to the anti tolerance effects of NMDA antagonists, recreational effects possibly yes.

 

[MeDieViL]

I'm totally getting similar results from Huperazine A. I've been taking 100 mcg twice daily for 4 days. I wonder if anyone else can relate to this w/r/t huperazine.

In case it's of interest to you, I've cut my alprazolam consumption in half. Not because I'm trying to give it up but because it's suddenly too potent. FWIW I have a 6-year daily alprazolam habit.

Interesting mate, so its NMDA antagonism seems to be strong enough to counteract tolerance too, very interesting stuff!

What results are you getting on amp with huperzine?

 

[MyDoorsAreOpen]

I wasn't aware memantine had any recreational potential on its own. For most people, at least from what I've been taught, the psychoactive effects of memantine are subtle enough to be unnoticeable for most people. Most other known NMDARAs (even magnesium), do a whole lot more than just antagonize NMDA receptors, and these actions are augmented and enhanced by their NMDA receptor action. Memantine, by contrast, pretty much just hits that one receptor, with a fairly low binding affinity, meaning any one molecule doesn't stay attached to the receptor and exert its effects very long before detaching. This is a good thing for people who want only the neuroprotective effects of NMDA receptor antagonism, and don't want to deal with any other effects, mental or bodily.

 

[MeDieViL]

^^ I was more referring to NMDA antagonists in general, like with DXM, tolerance to the recreational effects can occur but all reports consistently lack reporting a tolerance to the anti tolerance effect. Indeed memantine seems to be lacking in recreational effects only causing a unpleasant experine.

 

[seep]

What results are you getting on amp with huperzine?

Same as with DXM: takes the edge off while preserving the euphoria. No bruxism, no hyperkinesis, no anxiety, no obsessive thoughts or rumination.

A little less "speediness" though. Like, I'm not talking anyone's ears off or setting things on fire.

 

[Geaux Tigers!]

I am prescribed Lisdexamfetamine (Vyvanse) 70mg./day by my doctor. I have noticed that my tolerance has increased to Lisdexamafetamine.

What NMDA antagonist, besides Memantine, would be the best to use as a daily regimen to prevent tolerance buildup? I would do Memantine, but I don't have the means to procure it at this time.

I have looked into:

10ml. Delsym Extended Release daily
Chelated Magnesium 250mg daily
200 mcg. Huperzine A daily

Should I just get this? What OTC methods would you suggest to counteract my tolerance to Lisdexamfetamine?

 

[MyDoorsAreOpen]

Does anyone else yawn a lot on theanine?

 

[MeDieViL]

Is it known whether the NMDA antagonists in question will only reverse tolerance and thereby increase sensitivity to the level that could be seen before the receptors had been pharmaceutically stimulated OR will it actually increase sensitivity by separate mechanisms, therefore allowing an increased sensitivity past "natural" levels?? Damn I still haven't read through those publications...

It seems that receptor upregulation explains the tolerance prevention induced by NMDA antagonists, an overview of the references i was able to find:

NMDA antagonists and dopamine

(PMID: 1382178) Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat.
D2 binding studies carried out in MK-801 chronically treated (0.3 mg/kg/day per os, for 50 days) and control rats revealed an increased receptor density in treated animals without a significant change in receptor affinity.

(PMID: 7770607) Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.

(PMID: 10443547) Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists.
The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%.

(PMID: 10214758) Decreased striatal dopamine-receptor binding in sporadic ALS: glutamate hyperactivity?
In drug-naïve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole.

(PMID: 12832726 Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
We can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain.

(PMID: 10096038) Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP.

(PMID: 14997010) Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice.
The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.

NMDA antagonists and serotonin

(PMID: 9187317) Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT1A serotonin receptors in the rat brain.
It is concluded that single administration of MK-801 may alter the density of serotonergic 5-HT1A receptors and in consequence influence the function of the central nervous system associated with activation of 5-HT1A receptors.

Changes of GABA(A) receptor binding and subunit mRNA level in rat brain by infusion of subtoxic dose of MK-801.
Kim HS, Choi HS, Lee SY, Oh S.

College of Pharmacy, Chungbuk National University, Cheongju, 361-763, Chungbuk, South Korea.
Abstract
In the present study, we have investigated the effects of prolonged inhibition of NMDA receptor by infusion of subtoxic dose of MK-801 to examine the modulation of GABA(A) receptor binding and GABA(A) receptor subunit mRNA level in rat brain. It has been reported that NMDA-selective glutamate receptor stimulation alters GABA(A) receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunit. However, we have investigated the effect of NMDA antagonist, MK-801, on GABA(A) receptor binding characteristics in discrete brain regions by using autoradiographic and in situ hybridization techniques. The GABA(A) receptor bindings were analyzed by quantitative autoradiography using [3H]muscimol, [3H]flunitrazepam, and [35S]TBPS in rat brain slices. Rats were infused with MK-801 (1 pmol/10 microl per h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps (Alzet, model 2 ML). The levels of [3H]muscimol binding were highly elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, and cerebellum. However, the [3H]flunitrazepam binding and [35S]TBPS binding were increased only in specific regions; the former level was increased in parts of the cortex, thalamus, and hippocampus, while the latter binding sites were only slightly elevated in parts of thalamus. The levels of beta2-subunit were elevated in the frontal cortex, thalamus, hippocampus, brainstem, and cerebellar granule layers while the levels of beta3-subunit were significantly decreased in the cortex, hippocampus, and cerebellar granule layers in MK-801-infused rats. The levels of alpha6- and delta-subunits, which are highly localized in the cerebellum, were increased in the cerebellar granule layer after MK-801 treatment. These results show that the prolonged suppression of NMDA receptor function by MK-801-infusion strongly elevates [3H]muscimol binding throughout the brain, increases regional [3H]flunitrazepam and [35S]TBPS binding, and alters GABA(A) receptor subunit mRNA levels in different directions. The chronic MK-801 treatment has differential effect on various GABA(A) receptor subunits, which suggests involvement of differential regulatory mechanisms in interaction of NMDA receptor with the GABA receptors.

I'm still trying to find its effect on other receptors, like the GABAB receptor or other serotonine receptors.

 

[MeDieViL]

I am prescribed Lisdexamfetamine (Vyvanse) 70mg./day by my doctor. I have noticed that my tolerance has increased to Lisdexamafetamine.

What NMDA antagonist, besides Memantine, would be the best to use as a daily regimen to prevent tolerance buildup? I would do Memantine, but I don't have the means to procure it at this time.

I have looked into:

10ml. Delsym Extended Release daily
Chelated Magnesium 250mg daily
200 mcg. Huperzine A daily

Should I just get this? What OTC methods would you suggest to counteract my tolerance to Lisdexamfetamine?

Id say huperzine A looks like the best option, altough only seep reported succes with it, it definatly seems to be as potent as DXM looking at he's experience.

 

[MagickalKat777]

If Huperzine A can do this at 100mcg, it would make it the most potent NMDA antagonist known to man.

It fucks with acetylcholine though... Thanks but no thanks. Too many side effects.

Possible side effects include breathing problems, tightness in the throat or chest, chest pain, skin hives, rash, itchy or swollen skin, upset stomach, diarrhea, vomiting, hyperactivity and insomnia. Most adverse events were cholinergic in nature and no serious adverse events occurred.

(from wiki)

https://secure.wikimedia.org/wikipedia/en/wiki/Huperzine_A

I think I'll be sticking with memantine. Also, memantine FEELS like a dissociative... I don't know if this is because I just rapidly flew up to 40mg in a single week or not but it definitely feels like I'm on DXM or K, I just am not having any actual hallucinogenic effects.

I don't doubt that in a high enough dose, memantine would be hallucinogenic but it probably wouldn't be very pleasant.

So as of today its officially been 8 days since I cut my Valium from 40mg to 30mg and I've been having minimal withdrawal symptoms. Mostly just in my head - there have been no physical signs of withdrawal.

It was far too early to roll though - I did experience a lot of anxiety when I added MDA to my MDMA and then later added 2C-D and had the most intense OEVs of my life. So it does appear that NMDA antagonists also reduce tolerance to hallucinogenic phenethylamines, not just amphetamines.

 

[Geaux Tigers!]

Thanks for your insightful post about Huperzine A, MagickalKat777! You have definitely made me think twice about attempting a regimen of Huperzine A. Also, you have compounded my jealously with your access to Memantine.

However, I'm still dumbfounded as to what daily regimen of MNDA antagonist I should proceed with to reduce my Vyvanse tolerance.

If Huperzine A is so ineffective, what about a different suggestion? I'd appreciate any response. Thanks!

 

[Geaux Tigers!]

I was doing random reading in this forum. I came across another post from July from MagikalKat777.

Delsym. 30mg every twelve hours. Not very expensive and extremely effective. Two days at 60mg every twelve hours and I shaved 25% of my benzo dose on the third day.

Its certainly more effective than memantine but I took a psychedelic and was reminded why DXM is bad so I switched to memantine.

Would the suggestion he outlined be the most effective NMDA anatgonist regimen for me? If I solely did Delsym, would it be as effective as a cocktail of drugs, including magnesium (etc.)

 

[avcpl]

Went to 40mg today. I just took 131.4mg of moon rocks and I'm coming up fucking HARD! Memantine's effect on tolerance is NO JOKE! HOLY SHIT!

Would you say that the 40mg dose of memantine is needed for MDMA tolerance?

I ordered some and am trying to devise a schedule.

I was thinking 10mg a day for a week, up it to 20mg for a week then roll, or is that not aggressive enough? What would your recommendation be?

I'm one of the few that has not had roll improvement with piracetam and once took so much of it, I think it actually muted my roll). My MDMA tolerance is there, but not extreme; it's just really inconsistent even with most variables being equal. And my rolls are no where near the first few times (as is the case with most people), but not remedied by long breaks or good product or increasing doses..etc. and I don't think it's just lack of novelty either...

Thanks! Really enjoying this thread!