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

[MeDieViL]

Both seep and someone else (pmed me forgot username) have noticed that adding DXM to amp reverses tolerance to the locomotor and stimulating effects but not the euphoric effects, therefor i think a break is essential to reverse tolerance in the reward pathways, after wich DXM can be readded.

 

[MagickalKat777]

Be careful using DXM... it has nasty interactions with a lot of things. I stopped using Delsym after a bad reaction with 4-HO-MET and my 60mg twice a day DXM dose (was mild serotonin syndrome type effects).

I just received my memantine and reading the literature that came with it:

"Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors and for voltage dependent Ca2+, Na+, or K+ channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency."

I find it fascinating that it antagonizes 5HT3 - this is the receptor thought to be associated with vomiting and is what odansetron (Zofran) and other -setron drugs do. As many will know, these drugs are quite powerful anti-emetics. This makes me hopeful that memantine will prevent nausea and vomiting from certain substances.

The nicotinic acetylcholine receptor blockage explains why smokers tend to quit on memantine - nicotine specifically activates that receptor.

Further, the paperwork also says that it has 100% bioavailability and peak concentrations hit after 3 to 7 hours and the elimination half-life for the drug is 60-80 hours, with most of the drug (57-82%) being excreted unchanged. Also, CYP450 is not involved, unlike DXM.

Also, "the mode of action suggests that the effects of L-Dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with memantine. The effects of barbituates and neuroleptics may be reduced."

That explains part of the reduction of tolerance.

It also notes that the concomittant use of other NMDA antagonists (specifically mentioning amantadine, ketamine, and DXM) has not been evaluated and their use should be with caution due to the risk of pharmacotoxic psychosis.

The side effects seem rather minimal and no higher than placebo and they even speak of a 400mg overdose that "the patient experienced restlessness, psychosis, visual hallucinations, somnolence, stupor, and loss of consciousness. The patient recovered without permanent sequelae."

Sounds like higher doses become more like classic dissociatives. I wouldn't do that because of the extremely long half-life, however.

I see my doctor at 3 today and I'm going to tell him of my plans to start memantine and also ask for a low-dose prescription of Topamax to block AMPA in the last stage of benzo withdrawal.

 

[MeDieViL]

ive used memantine up to 80mg a day, was pretty much side effect free, its very easy to tolerate, it does potentiate several things such as dopaminergics. From what ive read it doesnt appear to be as strong as DXM for the reductionof tolerance while DXM is capable of reversing tolerance, mem seems to only dramatically slow it down. Its a very good med.

It also caused a huge difference in the MDMA comedowns, so i beleive it may also work for MDMA tolerance.

I highly recommend memantine instead of DXM.

 

[MagickalKat777]

DXM's activity profile is too broad-spectrum even if it reverses tolerance... and mem seems perfectly capable of reversing tolerance as well, just using higher doses or possibly just needing to take a longer break from the substance you're tolerant to.

I'm curious to see if memantine drops cathinone tolerance though - my cathinone tolerance is so high right now that I took 600mg of methylone and 400mg of M1 the other night and barely felt a thing until I took 2C-D, then I was rolling my ass off.

 

[MeDieViL]

Yes i know thats what i ment, sensitization occurs before tolerance occurs but its not really relevant, the fact they block sensitization doesnt mean they wont work against tolerance to the the euphoric effects.

Read this for more information behind the dynamics of sensitization, tolerance and addiction:
http://www.mesolimbic.com/article/addiction.html
http://www.nature.com/embor/journal/v7/n2/full/7400635.html
http://neuro.psychiatryonline.org/cgi/content/full/20/1/23

Those article mentions the major role of NMDA and CREB and addiction and tolerance, there does seem to be a CREB inhibit available namely curcumin:

Neuroreport. 2009 Jan 7;20(1):63-8.
Curcumin blocks chronic morphine analgesic tolerance and brain-derived neurotrophic factor upregulation.
Matsushita Y, Ueda H.

aDivision of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Abstract
This study was carried out based on the assumption that brain-derived neurotrophic factor (BDNF) may counterbalance the action of morphine in the brain. Morphine analgesic tolerance after daily administrations for six days was blocked by intracerebroventricular injection of anti-BDNF IgG on day 5, but not by administrations on days 1-4. Chronic morphine treatment significantly increased the expression of exon I and IV BDNF transcripts, indicating differential regulation of BDNF gene expression. Daily administration of the CREB-binding protein inhibitor curcumin abolished the upregulation of BDNF transcription and morphine analgesic tolerance. These results suggest that curcumin might be a promising adjuvant to reduce morphine analgesic tolerance, and that epigenetic control could be a new strategy useful for the control of this problem.

Ive experimented with curcumin for the past days (without memantine) and noticed it seemed to COMPLETELY abolish the depression of amphetamine comedowns, even after abusing it.
I havent experiment with it enough to make any conclusions regarding tolerance but my first impression seems to be very good.

I think it will be a very good add on to memantine. Be carefull tough, its a reverseble MAOA inhibitor (30%).

 

[MeDieViL]

DXM's activity profile is too broad-spectrum even if it reverses tolerance... and mem seems perfectly capable of reversing tolerance as well, just using higher doses or possibly just needing to take a longer break from the substance you're tolerant to.

I'm curious to see if memantine drops cathinone tolerance though - my cathinone tolerance is so high right now that I took 600mg of methylone and 400mg of M1 the other night and barely felt a thing until I took 2C-D, then I was rolling my ass off.

Yeah i'm curious as well, keep us updated!%)

 

[MagickalKat777]

Interesting. I have curcumin capsules that I bought as a supplement ages ago but never took.

Its MAO-A though? Hmmm...

 

[MeDieViL]

Interesting. I have curcumin capsules that I bought as a supplement ages ago but never took.

Its MAO-A though? Hmmm...

Yeah, altough i combined it with methylone without problem, its a reverseble inhibitor, tobacco smoke inhibits MAOA with 30% tough but ive got no idea how easily curcumin is displaced from the MAO enzyme.

I'm taking 500mg JARROW curcumin.

Perhaps use it with opiates/amps/benzo's first to see wheter it is of any added value for you.

 

[MeDieViL]

More refs and reports:

Continuous or intermittent cocaine administration: effects of amantadine treatment during withdrawal.
King GR, Joyner C, Ellinwood EH Jr.
Department of Psychiatry, Duke University Medical Center

Research indicates that daily cocaine injections produce sensitization to, while the continuous infusion of cocaine produces tolerance to, its behavioral and neurochemical effects. The effects of the continuous infusion of cocaine are consistent with the withdrawal syndrome reported by human cocaine abusers. The present experiment examined whether amantadine administrations during withdrawal from continuous or intermittent cocaine attenuate and/or eliminate the behavioral effects produced by these administration regimens. The rats were pretreated for 14 days with either continuous or intermittent daily injections of cocaine, and were then withdrawn from the pretreatment regimen for 7 days. On days 1-5 of the withdrawal period, half the subjects received a 5.0 mg/kg IP injection of amantadine, and the other half received a 20.0 mg/kg IP injection of amantadine. On day 7 of withdrawal from the cocaine pretreatment, all rats were given a 15.0 mg/kg IP injection of cocaine. Their behavior was rated according to the modified Ellinwood and Balster (6) scale for 60 min. The results indicated that amantadine treatment during withdrawal eliminated the tolerance normally associated with the continuous infusion of cocaine. In contrast, in both the saline control and daily injection subjects amantadine treatment during withdrawal resulted in a slight, but statistically significant, reduction in the behavioral effects of cocaine. The present results therefore indicate that low doses of amantadine should be considered as a potential pharmacotherapy for the early stages of cocaine withdrawal. Furthermore, the present experimental procedures may represent an effective screening methodology for potential cocaine pharmacotherapies.

PMID: 8208762 [PubMed - indexed for MEDLINE]

Yes, I can attest to the benefits of memantine in regards to amphetamine tolerance. Prior to using memantine, I attempted to minimize tolerance to Adderall with magnesium. Whilst it did yield limited success, memantine works far better for tolerance prevention; it also greatly enhances the rate of reversal to previously built tolerance if taken during a drug holiday.

And good luck in your re-sensitisation quest, mindsync. If you find naltrexone doesn't work like it should, I can PERSONALLY attest to the effectiveness of memantine, in both PREVENTION of tolerance and RE-SENSITISATION to opies. At least to hydrocodone, anyway (but, since they all work nearly the same way, it should work with just about any).

I took them nearly every day for a whole year and a half due to chronic chest pain, along with memantine and the occasional DXM experiment, and did NOT develop even so much as the slightest bit of tolerance.

Well, with the exception of psychological tolerance due to wearing off of novelty... Drugs just aren't as "fun" when you're used to taking them every day... even if they work CONSISTENTLY with NO tolerance...

I've been on 20mg memantine for several months now. I can attest to the benzo tolerance reduction. I can take .5mg alprazolam as-needed now and not have to fear the awful rebound anxiety the following day.

Also i would like to add that my first post may give a too positive view as some ppl DID end up getting tolerant, it seems that for optimal tolerance prevention 40mg a day is optimal, lower doses only slow it down.

 

[MagickalKat777]

Yeah, altough i combined it with methylone without problem, its a reverseble inhibitor, tobacco smoke inhibits MAOA with 30% tough but ive got no idea how easily curcumin is displaced from the MAO enzyme.

I'm taking 500mg JARROW curcumin.

Perhaps use it with opiates/amps/benzo's first to see wheter it is of any added value for you.

that's EXACTLY the same brand I have.

So I saw my doctor and after checking interactions, he gave me the greenlight on memantine but he doesn't want me to go any higher than 10mg a week - he sees no problem with the 40mg dose.

This is perfect since I just got a letter from my employer today informing me that they filled my position, essentially laying me off.

 

[seep]

Both seep and someone else (pmed me forgot username) have noticed that adding DXM to amp reverses tolerance to the locomotor and stimulating effects but not the euphoric effects

um, your sentence is a little confusing (I do appreciate that your native language is Belgian).

DXM preserved amp's euphoric effect, yes, but it definitely did not reverse tolerance to the locomotor effects. In fact, it calmed them a bit.

Additionally, it completely antagonized the stereotypical effects. In other words, I was not repeating the same phrase over and over and over and over and over and over and over: stuff like that. Stereotypical as in Asperger's stereotypy.

It also stopped the spontaneous crying.

Additionally, I would sometimes actually forget to take doses of amp: i.e. diminished craving.

I had to take a break from the DXM because of a weird GI event that felt something like severe acid reflux (which I've never had). The discomfort lasted for days.

 

[MeDieViL]

Ah okay, ive misread your last post in this thread.

 

[crOOk]

Oh niceness, I started reading about this very recently for two reasons:

1) NMDA receptors are fascinating and I'd love to research them in the future.

2) I started taking amphetamine sulfate orally, am planning to keep doing so for the next decade and am worried that tolerance is going to keep increasing. Since I started taking Magnesium citrate 3 weeks ago sensitivity hasn't been changing it seems (~1g per day dissolved in water, a ridiculous amount of actual Mg considering the size of that ligand).
I was considering to switch to DXM HBr 30mg per day for a few weeks and see if tolerance can actually be decreased that way.

I hope I'll have found out more once I have time to browse through those links.

Thank you!

Edit: Most excellent post MeDieViL, thank you very much!! I'll order some DXM right now! They only cost 2.48€ per 20caps here in Germany, that's nothing really even if it turns out I need 60mg per day! I'll still be at less than 10 Euros per month...

 

[MeDieViL]

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.

 

[MagickalKat777]

I started the memantine today. I took it with my 20mg valium dose and passed out for the next twelve hours. It appears its already potentiating it. Also, when I went to go get food a few minutes ago, I tried smoking a cigarette and it was absolutely disgusting. It also did not elevate my heart rate or blood pressure at all. It was as if I didn't get anything from the nicotine.

Such results were not expecting from the first dose. I took another 10mg with my night dose over valium about an hour ago and I'm extremely sleepy again.

I'm thinking about tossing in DXM as well since DXM seems to reduce tolerance while you're ON the drugs and memantine requires you to stop them it appears.

I wonder how my CREB would be involved in benzodiazepine. I talked to my doctor about AMPA and he does not feel comfortable giving me topiramate because it has a large side effect profile. He does support my use of memantine though. If it gets me off the benzos and back to "normal" then he is all for it.

 

[MeDieViL]

Psychological drug tolerance
The reward system is partly responsible for the psychological part of drug tolerance.
The CREB protein, a transcription factor activated by cyclic adenosine monophosphate (cAMP) immediately after a high, triggers genes that produce proteins such as dynorphin, which cuts off dopamine release and temporarily inhibits the reward circuit. In chronic drug users, a sustained activation of CREB thus forces a larger dose to be taken to reach the same effect. In addition it leaves the user feeling generally depressed and dissatisfied, and unable to find pleasure in previously enjoyable activities, often leading to a return to the drug for an additional "fix".[21]
A similar mechanism, interfering also with the dopamine system, but relying on a different transcription factor, CEBPB, has also been proposed. In this case dopamine release onto the nucleus accumbens neurons would trigger the increased synthesis of substance P which, in turn, would increase the dopamine synthesis in the VTA. The effect of this positive feedback is suggested to be dampened by repeated substance abuse.[22]

I havent read the paper wiki linked too yet but it makes complete sense to me as on curcumin i simply dont get amp depression comedown anymore, my binges are usually short lived tough but normally definatly make me depressed afterwards.

 

[MeDieViL]

Reversal of Triazolam Tolerance and Withdrawal-Induced Hyperlocomotor Activity and Anxiety by Bupropion in Mice
Dipesh Joshi, Pattipati S. Naidu, Amanpreet Singh, Shrinivas K. Kulkarni

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
Address of Corresponding Author

Pharmacology 2005;75:93-97 (DOI: 10.1159/000087189)

Key Words

Triazolam
Bupropion tolerance
Triazolam tolerance
Drug dependence
Triazolam withdrawal
Bupropion, anxiety
Abstract

Chronic administration of triazolam (0.25 mg/kg/day, i.p.) on days 1–8 and its withdrawal produced an anxiogenic reaction in mice as assessed in the mirrored-chamber test. Daily administration of bupropion (2 or 5 mg/kg, i.p.) prior to triazolam for 8 days prevented withdrawal-induced anxiety in mice. Triazolam withdrawal also induced a significant increase in the locomotor activity of mice indicating an anxiogenic response. Daily administration of bupropion (2 or 5 mg/kg) prior to triazolam for 8 days also prevented withdrawal-induced increased locomotor activity. In conclusion, chronic administration of bupropion (2 and 5 mg/kg) exhibited a significant protection against triazolam withdrawal-induced anxiety and hyperlocomotor activity in mice. The result suggests the protective effect of bupropion in the management of triazolam withdrawal reactions.

Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids.[79] Its mechanism of action is unknown, but likely linked to nAchR α3ß4 antagonism.

Wellbutrin is a α3ß4 antagonist too, seems that this antagonism of this receptors has some implications in drug tolerance, DXM appears to be an antagonist at that receptor too.

AFAIK memantine only antagonizes the alpha7 nicotinic receptor and not the α3ß4, this would explain why DXM is better at reversing tolerance in some cases then DXM, atlough memantine does appear to be efficient at reversing benzo tolerance and preventing further tolerance from occuring.

There's some good data on this receptor and addiction, will post more tomorrow, time for sleep soon!

 

[MagickalKat777]

Well at the 20mg dose, memantine is causing considerable respiratory suppression - should I take that as a sign that it is making me more sensitive to my valium dosing? I think I may need to cut back to 10mg a day as the respiratory suppression is rather significant.

 

[MeDieViL]

Cant you try to lower your benzo's doses? Memantine shouldnt do that so id say its the valium.

 

[MagickalKat777]

Yeah I cut the valium to 30mg a day instead of 40mg and kept the memantine at 20mg. Now I just need to see how my body does with it.

The weird thing is that the DXM did not cause this side effect and its not listed on memantine's side effect list. I may just be very sensitive to this drug??