# Evidence for NMDA antagonists blocking tolerance



## crayzyMed (Nov 2, 2006)

*NMDAR and opioid tolerance:*

(PMID: 19806811) Development of morphine induced tolerance and withdrawal symptoms is attenuated by lamotrigine and magnesium sulfate in mice
_From these results it is concluded that lamotrigine and magnesium sulfate alone or in combination could prevent the development of morphine tolerance and withdrawal symptoms. Glutamate release inhibitory effect of lamotrigine and its possible mechanism and property of magnesium, blocking the N-Methyl-D-Aspartate (NMDA) receptor calcium channel, is probably its mechanism on preventing morphine induced tolerance and dependence._

(PMID: 19764437) Anti-opioid action of glutamate-NMDA receptor systems underlying morphine analgesic tolerance
_The mechanisms underlying opioid tolerance are not fully understood, but appear to be comprised of two types of plasticity or counter-adaptation, at the cellular level and through neuronal circuits. Current studies mostly emphasize the cellular adaptation mechanisms, which include altered gene expression and receptor desensitization due to phosphorylation and endocytosis. However, the mechanisms underlying opioid tolerance and dependence are not always explained by cellular adaptation mechanisms alone. This review focuses on the plasticity in neuronal circuits achieved through an enhancement of so-called anti-opioid glutamate/NMDA receptor synaptic activities._

(PMID: 18819620) Evaluation the effects of dextromethorphan and midazolam on morphine induced tolerance and dependence in mice.
_From these results it may concluded that Dextromethorphan and midazolam alone or in combination could prevent the development of morphine induced tolerance and dependence. These effects can be related to the N-Methyl-D-Aspartate (NMDA) receptor antagonist behavior of Dextromethorphan and GABA-receptor agonist property of midazolam._

(PMID: 18177675) The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism
_Using the C-fibre reflex as a nociceptive response elicited by a wide range of stimulus intensities in the rat, we recently reported that a single treatment with (+)-HA966, a glycine site-specific NMDA receptor antagonist: (1) potentiates morphine antinociception; and (2) reverses an established morphine tolerance. _

(PMID: 17994223) NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats
_CONCLUSIONS: The results, together with previous research, suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization._

*NMDAR and ethanol tolerance:*

(PMID: 1596749) Effect of (+)MK-801 and ketamine on rapid tolerance to ethanol
_The findings suggest that NMDA antagonists block rapid tolerance by preventing some adaptation that occurs during intoxicated practice._

(PMID: 1831064) NMDA antagonist inhibits rapid tolerance to ethanol
_These data suggest that the known role of NMDA receptors in long-term synaptic facilitation may underlie the effect of learning in the development of tolerance to the motor-impairing and hypothermic effects of ethanol._

(PMID: 16790637) Ethanol-induced hypnotic tolerance is absent in N-methyl-D-aspartate receptor epsilon 1 subunit knockout mice
_Our results indicate epsilon1 subunit containing the NMDA receptor might be involved in the development of ethanol-induced hypnotic tolerance._

(PMID: 15153783) Acute tolerance to ethanol inhibition of NMDA-induced responses in rat rostral ventrolateral medulla neurons
_These data suggested that ethanol inhibition and subsequent tolerance development is associated with changed sensitivity to NMDA in the RVLM, which may play important roles in the ethanol regulation of cardiovascular function. _

(PMID: 8724445) Dizocilpine prevents the development of tolerance to ethanol-induced error on a circular maze test.
_Chronically, dizocilpine (0.075 and 0.15 mg/kg) prevented the development of tolerance to the effect of EtOH on error score, even though the lower dose of dizocilpine permitted tolerance to the effects of EtOH on running. These results suggest that NMDA receptor antagonists selectively inhibit tolerance to cognitive effects of ethanol even when the antagonists do not affect motor performance._

(PMID: 8545482) D-cycloserine enhances rapid tolerance to ethanol motor incoordination
_The enhancement of ethanol tolerance by D-cycloserine and the antagonism of this effect by ketamine cannot be attributed to changes in pharmacokinetics of ethanol. Taken together, these results confirm the participation of the NMDA receptor system in the development of tolerance to ethanol, and reinforce earlier findings about the involvement of learning in tolerance._

(PMID: 7938132) Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: importance of intoxicated practice
_Therefore, daily administration of the NMDA antagonists was necessary to block development of chronic tolerance. Daily injection of (+)MK-801 (0.25 mg/kg IP) failed to block chronic tolerance, but inclusion of a second dose of (+)MK-801 daily, and progressive increase of this second dose during the chronic treatment period did block chronic tolerance. Unlike (+)MK-801, ketamine does not have motor-impairing effects of its own, and does not potentiate those of ethanol; it was, therefore, used in the remaining experiments. _

(PMID: 7953754) Interaction between N-methyl-D-aspartate (NMDA) and serotonin (5-HT) on ethanol tolerance
_Earlier work from this laboratory had shown that 5-HT is involved in the development of tolerance to ethanol, and that enhancement of 5-HT levels by L-tryptophan accelerated tolerance development. To explore the possibility that NMDA receptors are involved in the 5-HT effect on tolerance, we examined the effect of a noncompetitive N-methyl-D-aspartate (NMDA) antagonist [(+)MK-801] on the ability of L-tryptophan to enhance tolerance to the effect of ethanol on tilt-plane test performance by the rat. L-Tryptophan treatment resulted in the development of rapid tolerance to a dose of ethanol that failed to produce such tolerance by itself. However, prior administration of (+)MK-801 blocked the L-tryptophan effect on rapid tolerance development, in a dose-dependent manner. These results suggest that NMDA receptors are involved in the 5-HT enhancement of ethanol tolerance._

(PMID: 8415841) Effect of D-cycloserine on rapid tolerance to ethanol
_These findings are further evidence that the NMDA system, which requires activation by the glycine receptor, plays a major role in the development of at least some forms of ethanol tolerance._

(PMID: 8453972) Blockade of chronic tolerance to ethanol by the NMDA antagonist, (+)-MK-801
_Tolerance to the effects of (+)-MK-801 itself did not occur over 2 weeks of treatment. These results suggest that NMDA receptors are involved in development of chronic tolerance to ethanol as shown previously with rapid tolerance._

(PMID: 8428601) Effect of NMDA receptor antagonists on rapid tolerance to ethanol
_Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses._


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## crayzyMed (Nov 2, 2006)

*Anecdotal reports*



> I've been using Delsym (dextromethorphan polistirex, DXM, a sustained-release preparation of DXM) to prevent amphetamine-tolerance as long as I've been taking them. So that would be about 8-9 months of use without breaks, and the proof is in the pudding.
> 
> I haven't developed any tolerance whatsoever to any of the drug's effects. The dose started at 30mg/day (of the XR formulation), but an extra 30mg capsule later in the day was added onto that after a few weeks because they seemed to wear off too quickly for me. I stayed on that until a couple months ago when I switched to the immediate-release formulation, which I find lasts about eight hours per dose (quite surprisingly!), with a come-up beginning at approximately T+0:15 hours post-dose, a pronounced effect at T+1:00 pursuant, the peak at T+2:00 through T+7:00, followed by a gentle comedown which ends about T+9:00. The only difference I find between the IR and XR formulations of the drug is actually that the IR form lacks the mid-dose sluggishness and consequent "second-wind". So one dose at 6AM *really* kicks in at 8AM, beginning to wear off at 1PM; taking the second dose at noon times everything just perfectly. If I'm planning on making rounds of the bars with friends at night or practicing/playing a gig with my band, I just pop an extra 30mg in the early evening as needed.
> 
> But back to the Delsym -- I used to take a full teaspoon of the 12-hour suspension twice daily (that's equivalent to 15mg Robitussin Maximum Strength Cough every six hours). This dose completely prevented any development of tolerance and *may* have even allayed some of the nastier stim side effects by antagonizing some excitatory neurotransmission via glutamate et al. For six weeks now though I've been taking Prozac at 40mg daily, which (along with its ultra-long-half-life metabolite, norfluoxetine) is among the most potent inhibitors of cytochrome P450 IID6 (aka debrisoquine 4-hydroxylase), along with quinidine and paroxetine. CYPIID6 is responsible for the metabolism via O-demethylation (removal of the methyl group at the sixth position in the structure) of dextromethorphan, which primarily acts upon PCP2 and sigma receptors, to the potent NMDA antagonist dextrorphan (DXO; the dextroratory form of the opioid levorphan, which is about equipotent to morphine). Thus I now take twice as much Delsym to ensure a more normal ratio of DXM to DXO in the blood. My doctor and all reseach I've done has assured me that this is perfectly safe (i.e. not nearly a dose sufficient to cause Olney's lesions, etc.). I would use another NMDA antagonist like Emenda (memantine HCl) if it were available to me, even if simply to avoid the simple carbohydrates in the syrup, but Medicaid will only cover three prescriptions monthly now that I've turned 21. I may, on the other hand, finally put my lab scale to good use and order pure dextrorphan tartrate from Sigma-Aldrich (0.5 grams = $63.30) so as to avoid the unnecessary PCP2/sigma activation associated with DXM. Another chemical I'm interested in is Merck, Sharpe and Dome Inc.'s (+)-MK-801 hydrogen maleate (dizocilpine hydrogen maleate), for which the Sigma-Aldrich "Cell Signalling and Neuroscience" catalog provides the following synopsis: "Highly potent and selective non-competitive NMDA receptor antagonist that acts at the NMDA receptor-operated ion channel as an open channel blocker. Inhibits behavioral sensitization to psychostimulants and ethanol." The cost is prohibitive, though -- $43.10/5mg.





> i just wanted to follow up on the subject of DXM and amphetamines. it's been my XP that a recommended dose of cough syrup, the only active ingredient being DXM, taken with 90mg XR adderall are as follows:
> 
> -much smoother onset, more of a ramp than a rocket
> 
> ...





> steady adderall xr use 30mg daily for months
> accidentally got scripted IR not XR and then had it fixed for XR but had an extra bottle of IR now
> Started using IR alternating with XR at times
> eventually started to crush XR and parachute on days I wanted them to come on stronger.
> ...





> Small doses of Ketamine taken before a dose of dexedrine definitely did wonders to keep tolerance at bay...
> 
> But now that I'm slightly the wiser, I simply take the small doses of Ketamine, and skip the amp altogether .





> i take 30-45mg about 45 minutes to an hour before ingesting an opiate. and yes it works. i have been abusing opiates for about 2-3 months or so now and my tolerance has stayed at a pretty intermediate level. with dxm+weed 35mg of hydrocodone has me nodding pretty nicely.





> I started using DXM in conjunction with opiate use about 6-7 months ago. I always use at least 45mg, but usually 60mg of DXM with every dose of opiate. It did not reverse tolerance, but it prevented tolerance from increasing. Before I started the DXM I to slowly increase dosage every month, but once I started the DXM, and even now, my dosage has remained identical and with even slightly stronger effect from the opiate dosage than 6 months ago(so I guess some reversal may have occured).
> 
> Note: I also use a dose of 600mg of Tagament and 100mg of Diphendydramine with each opiate dose along with the DXM.





> It's an NMDA antagonist so it reduced and prevents tolerance to opiates, and for some reason it increases the warmness, analgesia, and euphoria, for me atleast. That is at therapeutic doses. Anything above 90mg's will ruin an opiate high.





> actualy you guys ;like it or not, but i am right. ever try getting dexed up and then doing a line of coke? youll get so ****ing high its rediculous.
> dxm prevents tolerance from building to ALL the drugs i listed, thats fact. but it also makes them feel stronger. opiates i notice a HUGE difference, coke i notice the BIGGEST difference, and then speed and nicotine i guess. look into it if you dont believe me im not bull****ting you
> peace





> Memantine is good stuff. I've been taking 5mg a day for several weeks now, and i'm just now starting to see its tolerance prevention ability. I took one 20mg adderall XR + 5mg memantine this morning after a 4 day break from adderall and it has worked great all day. I lost the magic there for awhile but today the addy is working like it did during the first few months and this is just from 20mg.


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## crayzyMed (Nov 2, 2006)

And more....



> I'd have to agree with Klowns on this one. If only from personal anecdote. Yesterday, I started taking Robitussin for an awful cough with the flu but also had to complete a lot of work. Mind you I haven't felt particularly pleasant when taking Adderal in quite some time. Anyway I had taken about 50mg's of DXM an hour prior to taking the Adderal. Then took 40 mg IR. I should also note this is about double the dose I normally take. But god damn was I flying around it felt like some of the first few times ever taking it. Also, the last dose I took was around 10 pm last night and I have yet to fall asleep or even have any sign of sleepiness. This is strange because I can often fall asleep even after taking it late at night.





> dear good people
> I SUCCESFULLY use dxm every day in small doses to prevent tolerance from building to my pain pills, and occasional pods/seeds. now let me see
> i have been on opiates around ten years, but 4-5 years of CONSISTENT every day use of hydrocodone, and dxm. now, not ONCE in these years have i EVER asked my doctor to up my dose, (rather surprising to him i believe) and i still get EXCELLETN analgesia from just 1 7.5/325 hydrocodone a dose. sure i take mroe to get high every once in a while. but i dont actualy need more. and when i go on a binge and take a bunch, and run out on thursday, i cant get my pills till monday..............well when monday rolls around, i take ONE pill, smoke weed 15 minutes later and i am still STRAIGHT ****ED UP NODDING no joke. and no i am not a lightweight, i just dont like to run out of meds and be in withdrawal. idealy, 150-300 mg would be my choice of dose for the whole day, but alas, i cant get anyone to ****ign script me that much.
> i take anywhere from 30-120 mg dxm in the morning. i find polystyrex works better than bromide, it lasts all day, and it wont cause a sharp spike in psychoactive effects. (i wouldnt feel them anyways i use to drink 4 bottles of tussin a day for about 6 years and i had to go to serious rehab for that addiction). i havent fried out on it in almost exactly oen year. this drug IS a miracale drug, and no i wouldnt call it toxic to the brain. i would say it HELPS THE BRAIN, i mean, it is basicaly useful in EVERY sort of addiction, not just opiates, it can prevent tolerance to ALL kinds of drugs like caffeine nicotine amps, i mean ALL MANNER of drugs.
> ...





> I'm also inferring from the study that the researchers must consider DXM safe taken long-term. I mean, assuming 80mg morphine qid, we're talking 320mg of DXM daily -- still quite a bit shy of the gram recommended above, but 320mg is (for most people) a very psychoactive dose. I'm only taking 15mg and definitely feel it helps. I can't explain my lack of Ultram tolerance after 400mg/day for several months any other way.





> Well, I'm hanging on 40mg of Adderall with 3 NDMA antagonists: L-Theanine at 100-200mgs, DXM 60mg. Magnesium up to 1000mg. I first used 10 mg Adderall but without NDMA antagonists in two months had to jump up to 40 mgs. Then I started using the above and I can say that (I think) they work. I'd use acamprosate or memantine if i'd have access though.





> Hiya,
> 
> I wasn't able to look through all these studies to see if they gave any definitive information on human dosages of DXM which block NMDA receptors, but 60mg Delsym seems to work great for me -- there's no way in hell I'd still be finding relief from 60mg Adderall if it weren't for the DXM!





> Vince,
> 
> Memantine, for me at least, is effective for amphetamine tolerance. Whereas before it would poop out ofter about 3 days, leaving me wrung out and irritable, it now gives me a smooth effect (one dosage of 40mg. lasts about 12hours), that I can take every day- giving me energy, concentration, motivation and social confidence.
> 
> ...





> It's hardly utopia, but memantine to attenuate amphetamine tolerance to mood/motivational effects has worked for me (at 9 weeks in), and among a few others, this guy who documented his experiences with some extensiveness:
> 
> Like andrew I in the past acquired complete tolerance to the mood/motivational effects of amphetamine after about 2 or 3 days of chronic dosing, leaving a concentrative effect which for me (not everyone) always felt zombifying. These mood/motivational effects (in combination with the concentrative effect) are considerably more therapeutic for me.





> > I'm not concerned with development of tolerance as I've been able to maintain a constant effect from amphetamines for months now without raising dose. In all fairness, I do take 60mg Delsym (dextromethorphan polystirex) twice daily, which is quite likely preventing tolerance. My pdoc endorses the use of DXM to all his stimulant-treated patients now, ever since I brought it to his attention months ago. He's seeing many patients finally stabilized on doses of amphetamines whereas they used to escalate monthly or even weekly. It doesn't seem to be working as well for his patients taking methylphenidate.


I also found a negative report on ketamine, but this person was using recreational doses.



> I take (d)-amphetamine 15mg IR ~3 days per week. It works very well for SA and sometimes can make me very extroverted, but it's not a practical treatment as tolerance sets in if I use it more frequently.
> 
> After hearing many glowing reports about how memantine inhibits the development of amphetamine tolerance, I started taking it at 5mg for 4 days, and have been on 10mg/day since. On the 12th day of being on 10mg memantine, I took my usual 15mg dose of amph, and felt a powerful surge of euphoria, sociability, confidence, and was completely free of SA. It was just like taking amphetamine for the first time! Over the next 4 days, I took 15mg each morning but skipped one day. Each dose was just as powerful and efficacious, AND the duration was extended to ~7-8 hours! So this brings me to today, where I decided to reduce my amph dose to 10mg, and it's working even better than 15mg did before starting memantine.
> 
> Could memantine render amphetamine a practical longterm treatment for SA/social anhedonia (among many other disorders)? Looks like it may, but I'll have to give it the test of time. Anyone else have any experience with this regimen?





> Memantine has truly saved my life, i do not exaggerate. Although Memantine, by itself, doesn't offer me significant benefits (other than reduction of OCD) it pretty much, is the most important part of my regimen. It doesnt seem possible to actually prevent the tolerance to the Actual beneficial effects of Amphetamine, but....it is possible. I see no benefit in taking Amphetamine at all, if not combined with Memantine. I currently take 15 mg Memantine a day......5 and 10mg/day both significantly inhibited tolerance, however, only for a period of 2-4 weeks, I could take Amphetamine consistently (every day, 30mg) with its mood-elevating and anxiety-reducing and pro-social benefits, continuing to remain and be of use. When tolerance becomes a problem, i take short 2-5 day breaks from Amphetamine, and every time, my tolerance goes down significantly, and I am able to resume amphetamine, with its beneficial effects being much stronger again.
> 
> There is ALOT of evidence, that Memantine and other NMDA antagonists/glutamate antagonists reduce some of the neurotoxicity of Amphetamine. Some of the neurotoxicity will remain, regardless of NMDA antagonism.....however, glutamate itself, is responsible for a significant portion of amphetamine-induced neurotoxicity......honestly, Memantine appears to be, almost perfect, without any obvious shortcomings. It will only be a matter of time, before a negative effect of such, is discovered, but nevertheless, Its positive effects, appear to greatly outweigh its cost. Yay for memantine


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## Vini Vidi Vici (Jul 4, 2009)

i totally agree. low dose DXM use greatly potentiated all of my Adderrall and Vyvanse experiences. i took Vyvanse for about 3 weeks, and Adderrall for about another month or month and a half. i got tolerant to all the positive effects of adderrall in about 2 weeks. only way to make it work well consistently was to use DXM, preferably Delsym cough syrup. the longer i took DXM, the stronger the Adderral would get. If i took too high a dose of DXM, i would start feeling really happy, OCD would be completely obliterated, and id start touching people and talking and acting like a normal person who loves other people. 

but anyways, is amphetamine tolerance due to too much NMDA, or too little NMDA? ive heard completely conflicting answers from different people and posts.....one person said that amphetamine-induced psychosis could be caused by NMDA hypofuntion...


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> i totally agree. low dose DXM use greatly potentiated all of my Adderrall and Vyvanse experiences. i took Vyvanse for about 3 weeks, and Adderrall for about another month or month and a half. i got tolerant to all the positive effects of adderrall in about 2 weeks. only way to make it work well consistently was to use DXM, preferably Delsym cough syrup. the longer i took DXM, the stronger the Adderral would get. If i took too high a dose of DXM, i would start feeling really happy, OCD would be completely obliterated, and id start touching people and talking and acting like a normal person who loves other people.
> 
> but anyways, is amphetamine tolerance due to too much NMDA, or too little NMDA? ive heard completely conflicting answers from different people and posts.....one person said that amphetamine-induced psychosis could be caused by NMDA hypofuntion...


Thx for your contribution, i apreciate it

It is very interesting that you respond that good to a high dose of DXM, i would suggest to try memantine, it may work wonders for your anxiety and OCD. I also have experience with a recreational dose of DXM but i cant say it made me feel normal like amphetamine does.

NMDA antagonists do seem to be the solution for tolerance to all kinds of substances, which is pretty incredible.

I cant answer your last question, i dont know if the NMDA pathway is used to induce tolerance or that the NMDA receptors get more sensitive theirself.

Tomorrow my doc should make a decission wheter or not to prescribe memantine, i really hope he agrees.


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## euphoria (Jan 21, 2009)

I agree, there is enough evidence to say NMDA antagonists prevent tolerance to many drugs, perhaps not 100% but at least to a great extent. I was thinking the tolerance problem might just be switched to NMDA receptors, but these mounting numbers of user reports suggest otherwise (at low doses, like 60mg DXM / day).

Keeping magnesium levels up should also help, but I'd say stay below 400mg a day (supplemental) so you maintain a healthy level, not overdose (hypermagnesemia). Some people might not even need magnesium supplements, depending on diet and other factors.

You'd have to be careful to avoid cough syrups containing more active ingredients than DXM, and I don't know how safe constantly taking cough syrup is in general. Also there is the potential for severe drug interactions.


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## crayzyMed (Nov 2, 2006)

euphoria said:


> I agree, there is enough evidence to say NMDA antagonists prevent tolerance to many drugs, perhaps not 100% but at least to a great extent. I was thinking the tolerance problem might just be switched to NMDA receptors, but these mounting numbers of user reports suggest otherwise (at low doses, like 60mg DXM / day).
> 
> Keeping magnesium levels up should also help, but I'd say stay below 400mg a day (supplemental) so you maintain a healthy level, not overdose (hypermagnesemia). Some people might not even need magnesium supplements, depending on diet and other factors.
> 
> Some cough syrups contain more active ingredients than DXM, and in general I don't know how safe it is to ingest large quantities of cough syrup daily for so long. Also there is the potential for severe drug interactions.


I still am a but skeptical that magnesium is strong enough to control tolerance tough.

In my country you can buy cough syrup with only DXM or small capsules with fluid in (DXM only). You should allways be able to get something with DXM only. Cough syrop usually contains extra sugar wich isnt much of a problem. DXM is a pretty dirty drug tough and your right that it could interact with several meds, could cause serotonin syndrome in combination with SSRI's.

Memantine is the best option, downside is that its pretty expensive.


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## euphoria (Jan 21, 2009)

Magnesium probably wouldn't be strong enough alone (in normal doses), but it'd augment the neuroprotective effect of DXM etc..

DXM polistirex would give a slow release of DXM, and avoid the bromine in HBr.


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## crayzyMed (Nov 2, 2006)

euphoria said:


> Magnesium probably wouldn't be strong enough alone (in normal doses), but it'd augment the neuroprotective effect of DXM etc..


Yeah true.

And soon enough we'll know if nmda antagonists also prevent tolerance to serotonin releasers thx to our lab rat.
At least if my doc approves it tomorrow.

*NMDAR and stimulant tolerance:*

(PMID: 2671566) Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801

(PMID: 9560846) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

(PMID: 11915303) Alteration of neuronal activities following repeated administration of stimulants

*NMDAR and nicotine tolerance:*

(PMID: ) The NMDA antagonist dizocilpine (MK-801) attenuates tolerance to nicotine in rats
_These results suggest that the NMDA receptor may be involved in adaptation to both unconditioned and conditioned behavioural responses to nicotine._

(PMID: 18452252) The role of NMDA receptor antagonists in nicotine tolerance, sensitization, and physical dependence: a preclinical review
_The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation._

(PMID: B8032593) Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists
_The results suggest the involvement of NMDA receptors in adaptations of the behavioural and neurochemical effects of nicotine that occur as a result of repeated administration of the drug._

*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.
I_t 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._


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## euphoria (Jan 21, 2009)

I would guess it will prevent serotonergic tolerance. Incidentally, I read that DXM prevents some of MDMA's serotonergic toxicity, not that combining the two would be a good idea.


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## Vini Vidi Vici (Jul 4, 2009)

im asking my pdoc about Memantine of Friday....im also gonna ask about Riluzole


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## crayzyMed (Nov 2, 2006)

euphoria said:


> I would guess it will prevent serotonergic tolerance. Incidentally, I read that DXM prevents some of MDMA's serotonergic toxicity.


Memantine has also been shown to prevent toxiticy caused by MDMA and amphetamine like compounds.
http://www.ncbi.nlm.nih.gov/pubmed/18455739
http://cat.inist.fr/?aModele=afficheN&cpsidt=20062824

Altough they link this to the alpha-7 nicotinic receptors i think NMDA antagonism plays a role too as i also did read something about DXM protecting against MDMA's damage.



Vini Vidi Vici said:


> im asking my pdoc about Memantine of Friday....im also gonna ask about Riluzole


I hope he agrees man!.


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## crayzyMed (Nov 2, 2006)

rocknroll714 said:


> Nice post crayzyMed.
> 
> Riluzole is the **** from what I hear. Looking forward to seeing a report on it from you.


Thx.

Just called my doc and he hasnt made a decission yet about memantine, have to wait untill after the weekend.


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## Vini Vidi Vici (Jul 4, 2009)

rocknroll714 said:


> Nice post crayzyMed.
> 
> Riluzole is the **** from what I hear. Looking forward to seeing a report on it from you.


ya i know!! wait you mean **** as in good, right? i mean Riluzole looks so freaking awesome. It just obliterates Glutaminergic activity, and has been shown to help depression, OCD, and GAD,...unlike Memantine. im not sure how to bring it up to my pdoc....how am i supposed to explain why i want a drug for "Amyotrophic lateral sclerosis"..... im thinking i might try to compare/highlight its mechanism of action as being similiar to Benzodiazpines, without the associated addiction and tolerance and mental impairment..


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> ya i know!! wait you mean **** as in good, right? i mean Riluzole looks so freaking awesome. It just obliterates Glutaminergic activity, and has been shown to help depression, OCD, and GAD,...unlike Memantine. im not sure how to bring it up to my pdoc....how am i supposed to explain why i want a drug for "Amyotrophic lateral sclerosis"..... im thinking i might try to compare/highlight its mechanism of action as being similiar to Benzodiazpines, without the associated addiction and tolerance and mental impairment..


Just tell him you responded great to another NMDA antagonist before (DXM) and that its non addictive and doesnt build tolerance. Show him some positive studies about it.


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## Vini Vidi Vici (Jul 4, 2009)

memantine sounds like a good drug. however....isn't its NMDA antagonist activity rather on the Weaker side? and it also has a whole bunch of other possible actions....so if i took a whole lot, maybe id get really weird effects. ive read reports where people try to get high on it, and they end up feeling horrible. Riluzole sounds like it would be stronger and more natural in reducing NMDA activity....

also another completely random comment:- when i take Ambien or Zopiclone to go to sleep, many times, i experience euphoria and a "rush" that lasts for about 30 minutes- 3.00 hours. I don't get any of that "rush" from Benzos like Xanax. I have wondered what causes this antidepressant effect....it can be pretty potent sometimes.


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## Vini Vidi Vici (Jul 4, 2009)

crayzyMed said:


> Just tell him you responded great to another NMDA antagonist before (DXM) and that its non addictive and doesnt build tolerance. Show him some positive studies about it.


yeah.....im gonna bring tons of papers/research articles. . But my appointment is only 20-30 minutes, so im gonna have to stay completely on topic..... i was gonna talk about the NMDA system at my last appointment....i had it all planned out. but me being an idiot, i took Seroquel to sleep the night before the appointment. So at my appointment, i was so stoned and couldnt think straight,...couldnt organize my thoughts, so i didn't even bring it up.

DXM has always postively affected me...even by itself. I only take lower doses, ranging from i dunno, 20-150mg? but it kills my social anxiety for a couple hours, takes away alot of my depression, and helps a ton with OCD. i hope thats enough evidence for NMDA involvement in my psychodysfunctional state.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> memantine sounds like a good drug. however....isn't its NMDA antagonist activity rather on the Weaker side? and it also has a whole bunch of other possible actions....so if i took a whole lot, maybe id get really weird effects. ive read reports where people try to get high on it, and they end up feeling horrible. Riluzole sounds like it would be stronger and more natural in reducing NMDA activity....
> 
> also another completely random comment:- when i take Ambien or Zopiclone to go to sleep, many times, i experience euphoria and a "rush" that lasts for about 30 minutes- 3.00 hours. I don't get any of that "rush" from Benzos like Xanax. I have wondered what causes this antidepressant effect....it can be pretty potent sometimes.


I havent researched riluzole to know wheter it would be better then memantine, there are anecdotal reports on memantine howevery saying it works fine, so its mechanism of action appears to be good enough to block tolerance. And this text seems to suggest that because its only a moderate blocker of NMDA it only blocks "abnormal activation of NMDA receptors". Which may be just what it takes to block tolerance.

I'd say its differend properties are fine, 5HT3 antagonism isnt a bad thing either and antagonism of the nicotine receptor seems to block neurotoxiticy of amphetamine deratives.
My preference goes to memantine.



> http://www.jaoa.org/cgi/content/full/106/6/358
> 
> *Memantine: The Next Trend in Academic Performance Enhancement? *
> *KEN S. OTA, OMS III; TINA GODWIN, OMS II *
> ...


And yeah i've also seen a a report saying it sucks to get high on, doesnt matter for me tough as i'm not taking it for that purpose.

Cant answer your last question.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> yeah.....im gonna bring tons of papers/research articles. . But my appointment is only 20-30 minutes, so im gonna have to stay completely on topic..... i was gonna talk about the NMDA system at my last appointment....i had it all planned out. but me being an idiot, i took Seroquel to sleep the night before the appointment. So at my appointment, i was so stoned and couldnt think straight,...couldnt organize my thoughts, so i didn't even bring it up.
> 
> DXM has always postively affected me...even by itself. I only take lower doses, ranging from i dunno, 20-150mg? but it kills my social anxiety for a couple hours, takes away alot of my depression, and helps a ton with OCD. i hope thats enough evidence for NMDA involvement in my psychodysfunctional state.


Sounds like memantine or another NMDA antagonist is just what you need I've read about someone feeling completely normal on DXM before, strange how we all react differendly to differend treatments.


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## Vini Vidi Vici (Jul 4, 2009)

word man...i mean i really don't have a preference towards riluzole, especially since ive not had any experience with either. memantine might even be better, i mean since it doesnt block all the NMDA channels and stuff, only those which are over-excited. so you could still think straight and stuff,....


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> word man...i mean i really don't have a preference towards riluzole, especially since ive not had any experience with either. memantine might even be better, i mean since it doesnt block all the NMDA channels and stuff, only those which are over-excited. so you could still think straight and stuff,....


The first week or 2 of starting memantine it may decrease short term memory and cause brainfog but after that those side effects fade from what i've read. And some studies suggest it improves cognition, wich is awesome:yes.

But i dunno riluzole may also be great, just dont know much about it.


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## Vini Vidi Vici (Jul 4, 2009)

thats awesome! if it decreases short term memory and causes brain fog....that means that it is actually decreasing NMDA activity. so it actually works strong enough to induce a perceptual change. 

after doing some research on Riluzole, i doubt my insurance company will cover it. Sanofi aventis, the maufacturer, kind of has a monopoly or sorts on the ALS market, so maybe this would explain why 50 tablets of Riluzole cost $1,000. i don't know how i would get my doc to prescribe it, and my insurance to cover it....even if i got it id still have 2 pay 250$.

im gonna go for the memantine. and maybe ask for Klonopin also.... i need to drastically lower the level of NMDA activity, even if nonselectively, to function properly. someone needs to make more NMDA antagonists/ glutamate destroyers/glutamate reuptake enhacers-(like Riluzole)


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## crayzyMed (Nov 2, 2006)

Damn, if riluzole is that expensive i would def go with memantine. Yeah NMDA antagonists really need to get more downstream for anxiety disorders and marketed for tolerance prevention.


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## Vini Vidi Vici (Jul 4, 2009)

cool article....ive been able to find quite a few different references to Riluzole, i dunno if they are all the same source requoted, but still, Riluzole is awesome. 
I need to figure out a way to bypass the around 700$ or so a month cost of it...


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## Vini Vidi Vici (Jul 4, 2009)

i found this antibiotic thingy that looks like it does something similiar (maybe) to riluzole--- Ceftriaxone ... it enhances glutamate uptake activity and is neuroprotective through some complicated mechanism which i didn't understand from the article ---http://www.jbc.org/content/283/19/13116.abstract


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## Vini Vidi Vici (Jul 4, 2009)

i just got back from my doctors appointment....unfortunately, i did not get memantine. but she had heard of it, and she used it to treat a patient who was electrocuted. and i told her about the beneficial effects of benzo tolerance and OCD/anxiety/depression. but i did get Klonopin, which I hope** is a good thing. i dunno if it will really cure or help me, cuz xanax didn't really do anything for me other than decrease all my brain functions. but klono and xanax do help me to function in social situations. i can still try N-acetyl -cysteine, maybe that will lower glutamate.... ... i wish i had a huge list of all and any NMDA antagonists/modulators.


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## gillettecavalcad3 (Jul 9, 2009)

Mate, Clonazepam is the daddy of the benzo's, .....and that is coming from someone who has tried them all.

I hope you have as much luck as I have had with Clonazepam.

Wonder drug.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> i just got back from my doctors appointment....unfortunately, i did not get memantine. but she had heard of it, and she used it to treat a patient who was electrocuted. and i told her about the beneficial effects of benzo tolerance and OCD/anxiety/depression. but i did get Klonopin, which I hope** is a good thing. i dunno if it will really cure or help me, cuz xanax didn't really do anything for me other than decrease all my brain functions. but klono and xanax do help me to function in social situations. i can still try N-acetyl -cysteine, maybe that will lower glutamate.... ... i wish i had a huge list of all and any NMDA antagonists/modulators.


Maybe find a new doc if the klonopin doesnt work out? It looks like memantine could work wonders for you  and memantine is also a long term treatment which can (and should) be taken daily. If it works a much better option than just klonopin.


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## Vini Vidi Vici (Jul 4, 2009)

rocknroll714 said:


> I've tried alprazolam, clonazepam, and lorazepam, and clonazepam is by far my favorite. +1 for kpin.


im feeling more optimistic now... what was really funny was, it wasn't hard to get K-pin at all. i was thinking at least i would have to beg or argue or something to get it, but i barely even mentioned it and my pdoc was like yeah thats a great idea.


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## crayzyMed (Nov 2, 2006)

I wish benzo's worked for me, my mum has a huge stock of them lol.


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## Vini Vidi Vici (Jul 4, 2009)

wow they don't work at all? like do they even make you tired?


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> wow they don't work at all? like do they even make you tired?


If i take around 10 or something i get slightly tired. The first time i had a benzo (akton was it called in belguim is beleive, it was more of a rare one) i took 1 more every day ending me to take huge ammounds in the end (5pills at once several times a day) without any succes, just mildly tired. Experiments with all other kinds of benzo's produce the same result.
I do respong on GHB wich makes me euphoric and is a great thing to get high twice a day but it doesnt do a thing for my social anxiety, it really doesnt affect it all.
Alcohol is garbage too.

Uppers on the other hand.. They leave me cured long after they stopped working. Hence my crazy experiments


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## Vini Vidi Vici (Jul 4, 2009)

thats really intresting...uppers seem to make me a ton worse after they wear off, like caffeine, nicotine, amphetamine, and other stuff. do you mean uppers as in Serotonergic uppers? Benzos and alcohol both help me alot, but then when they wear off, im a ton worse.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> thats really intresting...uppers seem to make me a ton worse after they wear off, like caffeine, nicotine, amphetamine, and other stuff. do you mean uppers as in Serotonergic uppers? Benzos and alcohol both help me alot, but then when they wear off, im a ton worse.


MDMA --> If i take a few pills when partying i feel cured untill 6 o clock in the evening the next day. Just completely cured, no high just sober and cured.

Amphetamines do the same thing, altough with awfull paranoia, i wonder why amphetamines make me paranoid so fast, i think that i also have a problem in my serotonin system so the amphetamine paranoia isnt getting prevented or something. Amphetamines and MDMA also completely abolish OCD.

Cafeine --> Causes mild improvent in social anxiety and OCD.

Nicotine --> Complete garbage, a few spliffs and i feel like complete ****, wanting to puke and stuff, however on MDMA i can enjoy a sigaret.


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## crayzyMed (Nov 2, 2006)

Added a small text about amphetamines and memantine, didnt write it myself but may be of intrest.


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## Vini Vidi Vici (Jul 4, 2009)

crayzyMed said:


> MDMA --> If i take a few pills when partying i feel cured untill 6 o clock in the evening the next day. Just completely cured, no high just sober and cured.
> 
> Amphetamines do the same thing, altough with awfull paranoia, i wonder why amphetamines make me paranoid so fast, i think that i also have a problem in my serotonin system so the amphetamine paranoia isnt getting prevented or something. Amphetamines and MDMA also completely abolish OCD.
> 
> ...


never tried MDMA, but I want to once im not on MAOIs, and if i can get all the neuroprotective stuff ...

Nicotine has always been super helpful for me in reducing anxiety/OCD and depression, but sometimes, i have completely differing responses....nicotine gum helps me alot, but cigars and cigarettes always make me worse. the lower the dose, the better

Caffeine helps me with everything, OCD, depression, and anxiety, but then agian, my response to it differs almost daily. amphetamine always makes me crazy/psychotic/paranoid...but it helps alot with my depression


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> never tried MDMA, but I want to once im not on MAOIs, and if i can get all the neuroprotective stuff ...
> 
> Nicotine has always been super helpful for me in reducing anxiety/OCD and depression, but sometimes, i have completely differing responses....nicotine gum helps me alot, but cigars and cigarettes always make me worse. the lower the dose, the better
> 
> Caffeine helps me with everything, OCD, depression, and anxiety, but then agian, my response to it differs almost daily. amphetamine always makes me crazy/psychotic/paranoid...but it helps alot with my depression


Yeah amphetamines also induce terrible paranoia for me, i dont know wheter this would happen with dexedrine but i tried street amphetamine for a while in low doses all it did was induce paranoia. They do make me feel completely normal tough in recreational doses but i think i also need serotonin, serotonin seems to buffer out the paranoia caused by dopamine.

This is way i think things like 4FMP are the key for me:yes.
Cafeine is also great but its effect is waay to mild.

I never tried nicotine in gum form tough, may give it a try.


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## Vini Vidi Vici (Jul 4, 2009)

interesting article ::



> The β-lactam antibiotic ceftriaxone inhibits physical dependence and abstinence-induced withdrawal from cocaine, amphetamine, methamphetamine, and clorazepate in planarians
> 
> Ceftriaxone (a β-lactam antibiotic) has recently been identified as having the rare ability to increase the expression and functional activity of the glutamate transporter subtype 1 (GLT-1) in rat spinal cord cultures. GLT-1 has been implicated in diverse neurological disorders and in opioid dependence and withdrawal. It has been speculated that it might also be involved in the physical dependence and withdrawal of other abused drugs, but demonstration of this property can be difficult in mammalian models. Here, we demonstrate for the first time using a planarian model that ceftriaxone attenuates both the development of physical dependence and abstinence-induced withdrawal from cocaine, amphetamine, methamphetamine, and a benzodiazepine (clorazepate) in a concentration-related manner. These results suggest that physical dependence and withdrawal from several drugs involve a common - β-lactam-sensitive - mechanism in planarians. If these findings can be shown to extend to mammals, β-lactam antibiotics might represent a novel pharmacotherapy or adjunct approach for treating drug abuse or serve as a template for drug discovery efforts aimed at treating drug abuse, recovery from drug abuse, or ameliorating the withdrawal from chronic use of therapeutic medications.


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## Vini Vidi Vici (Jul 4, 2009)

from wikipedia:



> Astrocytes seem to utilize reuptake mechanisms for a neuroprotective role. Astrocytes use GLT-1 to remove glutamate from the synapse. GLT-1 knockout mice were more prone to lethal and spontaneous seizures and acute brain injuries among the cortex. These effects could be linked to increased concentrations of glutamate in the brains of GLT-1 knockout mice, analyzed post-mortem[8].


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## crayzyMed (Nov 2, 2006)

Interesting, gonna check it all out tomorrow.


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## Vini Vidi Vici (Jul 4, 2009)

would it be a dumb idea to fake symptoms of Amyotrophic lateral sclerosis, to try and get Riluzole, or is it just wrong? i mean id be getting it for a legitimate purpose anyway, OCD/anxiety/depression,.... cuz if my NMDA system is as OverActive as it could be, would i get just get tolerant to the NMDA-antagonism of Memantine? id think that my brain would just do the same as it does with anything else...upregulate the blocked receptors, somewhat more slowly due to NMDA's mediation of tolerance.....


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> would it be a dumb idea to fake symptoms of Amyotrophic lateral sclerosis, to try and get Riluzole, or is it just wrong? i mean id be getting it for a legitimate purpose anyway, OCD/anxiety/depression,.... cuz if my NMDA system is as OverActive as it could be, would i get just get tolerant to the NMDA-antagonism of Memantine? id think that my brain would just do the same as it does with anything else...upregulate the blocked receptors, somewhat more slowly due to NMDA's mediation of tolerance.....


Anecdotal reports do not seem to mention a tolerance to NMDA antagonis, memantine is a long term med anyway and i've seen alot reports about ppl taking a really long time and it still being as effective.

And i do think thats a bad idea, just try to go to differend docters as i suggested, that would be the easiest imo. (I allways tell the doc i used to order that med from the internet and that it works while many other treatments i got prescribed failed and that i rather have it prescribed, allways does the trick for me.)


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## Vini Vidi Vici (Jul 4, 2009)

crayzyMed said:


> Anecdotal reports do not seem to mention a tolerance to NMDA antagonis, memantine is a long term med anyway and i've seen alot reports about ppl taking a really long time and it still being as effective.
> 
> And i do think thats a bad idea, just try to go to differend docters as i suggested, that would be the easiest imo. (I allways tell the doc i used to order that med from the internet and that it works while many other treatments i got prescribed failed and that i rather have it prescribed, allways does the trick for me.)


NIce! dude...i was thinking about doing that. but then, my dad said i shouldnt use that approach,... i think im gonna try that. i mean....its true, if i don't get memantine from a doc, i am gonna order it online...from a website where i will have to pay $$ for it, and where the quality is questionable. Very good suggestion dude, i almost had forgotten about that. thats what im bring up at my next appointment on December 11... i dunno if i can get my parents to let me go to more than one doc at the same time, unless i very very clearly described the medicines i need and why i need a specific combination of meds to them (my parents). However, after i get Memantine (or riluzole...but im thinking memantine is actually gonna happen)...all i will really need to acheive full remission (if Memantine isn't enough, which it might be) of symptoms is something similiar or = to *(2S)-2-[(-)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol*


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## k0mnatad0t (Nov 15, 2009)

So have any anxiety sufferers actually experimented with this memantine yet or are you guys going to be the guinea pigs for us?


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## crayzyMed (Nov 2, 2006)

k0mnatad0t said:


> So have any anxiety sufferers actually experimented with this memantine yet or are you guys going to be the guinea pigs for us?


I will be a guinea big.


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## Vini Vidi Vici (Jul 4, 2009)

ill be the next one...if crazymed survives. good luck dude, if you die i will officialy change my name from ViniVidiVici to Crazymed the 2nd in honor of you. crazymed is a hero. im not being sarcastic, not really, because well, i don't really wanna try memantine without knowing almost firsthand what it really is like....


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## crayzyMed (Nov 2, 2006)

vini vidi vici said:


> ill be the next one...if crazymed survives. Good luck dude, if you die i will officialy change my name from vinividivici to crazymed the 2nd in honor of you. Crazymed is a hero. Im not being sarcastic, not really, because well, i don't really wanna try memantine without knowing almost firsthand what it really is like....


lol:d.


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## Vini Vidi Vici (Jul 4, 2009)

Biperiden and Budipine = NMDA antagonists.....i think Biperiden is still available. but Biperiden is an anticholinergic, also...

Amantadine looks ok...but i guess its weak. it releases DA and NA also, but it too is anticholinergic....Rimantadine, i dunno about that one........i just realized that they all sound the same...Memantine, amantadine, lol


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## Vini Vidi Vici (Jul 4, 2009)

i can't wait till my next doc appointment to get memantine....i just hope i dont wimp out and get too scared to ask and prod for it.......if i took memantine with an SSRI, which i probably am gonna end up doing, the 5ht3 antagonism wouldnt matter. Also, recently, every time i smoke nicotine i get sick and feel terrible. So..the nACHr antagonism might be good. and....il only have to take memantine once like every 3 days, and it would probably still build up in my system......if memantine works, image how much stuff it could help/prevent--- depression, OCD, my K-pin tolerance, my future Dexedrine tolerance (if i get it), ......glutamate sucks. why does it even exist....


and also, i am discontinuing Parnate, as of today. It is giving me akathisia, making me really really depressed, and i can't enjoy or focus on anything, i also have no ability to feel emotion. Parnate is lame....and i can't take it with Agomelatine cuz Agomelatine would cost too much. So when i go to my, doc i wont have 2 worry about the washout period


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> i can't wait till my next doc appointment to get memantine....i just hope i dont wimp out and get too scared to ask and prod for it.......if i took memantine with an SSRI, which i probably am gonna end up doing, the 5ht3 antagonism wouldnt matter. Also, recently, every time i smoke nicotine i get sick and feel terrible. So..the nACHr antagonism might be good. and....il only have to take memantine once like every 3 days, and it would probably still build up in my system......if memantine works, image how much stuff it could help/prevent--- depression, OCD, my K-pin tolerance, my future Dexedrine tolerance (if i get it), ......glutamate sucks. why does it even exist....
> 
> and also, i am discontinuing Parnate, as of today. It is giving me akathisia, making me really really depressed, and i can't enjoy or focus on anything, i also have no ability to feel emotion. Parnate is lame....and i can't take it with Agomelatine cuz Agomelatine would cost too much. So when i go to my, doc i wont have 2 worry about the washout period


Allright, i hope you do get the memantine man. I do suggest to take memantine daily tough. Not sure wheter it would work if you take it once every 3 days.


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## Vini Vidi Vici (Jul 4, 2009)

> *Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine*
> 
> Cocai*n*e produces a persiste*n*t reductio*n* i*n* cysti*n*e-glutamate excha*n*ge via system xc- i*n* the *n*ucleus accumbe*n*s that may co*n*tribute to pathological glutamate sig*n*ali*n*g li*n*ked to addictio*n*. System xc- i*n*flue*n*ces glutamate *n*eurotra*n*smissio*n* by mai*n*tai*n*i*n*g basal, extracellular glutamate i*n* the *n*ucleus accumbe*n*s, which, i*n* tur*n*, shapes sy*n*aptic activity by stimulati*n*g group II metabotropic glutamate autoreceptors. I*n* the prese*n*t study, we tested the hypothesis that a lo*n*g-term reductio*n* i*n* system xc- activity is part of the plasticity produced by repeated cocai*n*e that results i*n* the establishme*n*t of compulsive drug seeki*n*g. To test this, the *cysteine* prodrug _*N*_-*acetyl**cysteine* was admi*n*istered before daily cocai*n*e to determi*n*e the impact of i*n*creased cysti*n*e-glutamate excha*n*ge o*n* the developme*n*t of plasticity-depe*n*de*n*t cocai*n*e seeki*n*g. Although _*N*_-*acetyl**cysteine* admi*n*istered before cocai*n*e did *n*ot alter the acute effects of cocai*n*e o*n* self-admi*n*istratio*n* or locomotor activity, it preve*n*ted behaviors produced by repeated cocai*n*e i*n*cludi*n*g escalatio*n* of drug i*n*take, behavioral se*n*sitizatio*n*, a*n*d cocai*n*e-primed rei*n*stateme*n*t. Because se*n*sitizatio*n* or rei*n*stateme*n*t was *n*ot evide*n*t eve*n* 2-3 weeks after the last i*n*jectio*n* of _*N*_-*acetyl**cysteine*, we exami*n*ed whether _*N*_-*acetyl**cysteine* admi*n*istered before daily cocai*n*e also preve*n*ted the persiste*n*t reductio*n* i*n* system xc- activity produced by repeated cocai*n*e. I*n*teresti*n*gly, _*N*_-*acetyl**cysteine* pretreatme*n*t preve*n*ted cocai*n*e-i*n*duced cha*n*ges i*n* [35S]cysti*n*e tra*n*sport via system xc-, basal glutamate, a*n*d cocai*n*e-evoked glutamate i*n* the *n*ucleus accumbe*n*s whe*n* assessed at least 3 weeks after the last _*N*_-*acetyl**cysteine* pretreatme*n*t. These fi*n*di*n*gs i*n*dicate that _*N*_-*acetyl**cysteine* selectively alters plasticity-depe*n*de*n*t behaviors a*n*d that *n*ormal system xc- activity preve*n*ts pathological cha*n*ges i*n* extracellular glutamate that may be *n*ecessary for compulsive drug seeki*n*g.


http://www.jneurosci.org/cgi/content/full/27/51/13968


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## Vini Vidi Vici (Jul 4, 2009)

Vini Vidi Vici said:


> http://www.jneurosci.org/cgi/content/full/27/51/13968


this looks interesting, i still odnt understand exactly what NAC does, but it appears to do something...like preventing cocaine sensitization/drug seeking behaviors, dose escalation,.....looks interesting. I saw something on bluelight where someone said NAC blunted amphetamine effects greatly...i dunno. It would make sense that it wouldn't decrease Cocaines effects obviously, but still decrease amphetamines effects.... i havnt taken any NAC since i started dexedrine 2 days ago..


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## euphoria (Jan 21, 2009)

So in conclusion, memantine prevents tolerance to pretty much everything .


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## crayzyMed (Nov 2, 2006)

Looks like it, will update with personal experience's soon.


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## crayzyMed (Nov 2, 2006)

Heh:


> The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans.
> Collins ED, Ward AS, McDowell DM, Foltin RW, Fischman MW.
> 
> Division on Substance Abuse, New York State Psychiatric Institute, New York, USA. [email protected]
> Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. *Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. *These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.


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## euphoria (Jan 21, 2009)

^ lol. So memantine prevents tolerance to agonists, but does it prevent upregulation in response to antagonists? I've heard nicotinic receptors upregulate with memantine use. And what about inverse agonists?


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## crayzyMed (Nov 2, 2006)

euphoria said:


> ^ lol. So memantine prevents tolerance to agonists, but does it prevent upregulation in response to antagonists? I've heard nicotinic receptors upregulate with memantine use. And what about inverse agonists?


It only prevents tolerance to drugs that release glutamate, not agonists or antagonists per se.


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## crayzyMed (Nov 2, 2006)

Ive been thinking that CCK2 may be an interesting target for tolerance prevention too

Lets see what we know:


> Abstract
> 
> The ability of a pretreatment with the cholecystokininB-receptor (CCKB) antagonist L-365,260 to prevent the development of morphine dependence was studied in normal and neuropathic (unilateral peripheral neuropathy) rats. A 4-day pretreatment regimen with two daily s.c. injections of either saline+saline, saline+morphine (3.0 mg/kg) or L-365,260 (0.2 mg/kg)+morphine was used, and withdrawal was precipitated by an injection of naloxone (1.0 or 2.0 mg/kg i.v.) at 24 h after the last pretreatment injection. After pretreatment with morphine alone, physical dependence developed in both normal and neuropathic rats. However, the incidence of teeth chattering and ptosis was higher in neuropathic rats. *Pretreatment with the combination of L-365,260 and morphine prevented the expression of teeth chattering, ptosis, diarrhea, writhing and piloerection, but was devoid of effects on the exploratory activity among both groups of rats. These results suggest that endogenous CCK acting on CCKB-receptors may be involved in the development of morphine dependence both in normal and neuropathic rats.*





> The effects of the selective CCK-A antagonist L-365,031 and the selective CCK-B antagonist L-365,260 on morphine analgesia and opiate tolerance and dependence in rats were examined. L-365,031 and L-365,260 had no effect on baseline pain thresholds in the radiant heat tail flick test but enhanced analgesia induced by a submaximal dose of morphine (4 mg/kg). Similarly, L-365,260 did not effect pain thresholds in the paw pressure test but enhanced morphine analgesia in this model. Rats injected twice daily for 6 days with incremental doses of morphine became tolerant to the analgesic effects of the drug. *Twice daily injections of either 8 mg/kg L-365,031 or 0.2 mg/kg L-365,260 prevented the development of tolerance to morphine analgesia.* In contrast, L-365,260 had no influence on the development of opiate dependence in these animals, as assessed by naloxone-precipitated withdrawal. The results of the present study, when considered together with previous data, indicate that the rank order of potency of non-peptide CCK antagonists for enhancing morphine analgesia is L-365,260 greater than MK-329 greater than L-365,031. This rank order correlates well with the potency of the antagonists in blocking CCK-B receptors in rodents and suggests that CCK/opiate interactions in this species are mediated by CCK-B receptors.


So CCKB antagonists appear to inhibit opiate withdrawal and tolerance in mice, ive been thinking that it could do the same thing with amphetamines, this is what i came up with:



> Self-administration of intravenous amphetamine: effect of nucleus accumbens CCKB receptor activation on fixed-ratio responding.
> Bush DE, DeSousa NJ, Vaccarino FJ.
> 
> Department of Psychology, University of Toronto, Ontario, Canada.
> RATIONALE: The mesolimbic dopamine (DA) system is implicated in psychostimulant drug self-administration. The neuropeptide cholecystokinin (CCK) is co-localised with DA and inhibits nucleus accumbens (NAcc) DAergic neurotransmission via CCKB receptors. OBJECTIVES: The present experiment was designed to examine the effects of intra-NAcc CCKB receptor stimulation on fixed-ratio (FR) amphetamine self-administration. METHODS: Wistar rats with intravenous catheters and NAcc cannulae were trained to self-administer amphetamine under a FR3 schedule of reinforcement. Animals performing stable self-administration were microinjected with pentagastrin and assessed during 3-h sessions. RESULTS: Intra-NAcc pentagastrin dose dependently increased amphetamine intake. CONCLUSIONS: *These results are consistent with the notion that NAcc CCKB receptor activation attenuates amphetamine reward.*





> Interaction of CCKB receptors with amphetamine in responding for conditioned rewards.
> Josselyn SA, Vaccarino FJ.
> 
> Department of Psychology, University of Toronto, Ontario, Canada.
> Cholecystokinin (CCK) has been localized in the nucleus accumbens (NAC) where it may interact with dopamine neurotransmission. NAC dopamine is involved in the control over behavior produced by conditioned rewards. The present experiment tested the whether blockade of endogenous CCKB receptors with L-365,260 (0.1 mg/kg, IP) potentiates bar pressing for stimuli previously associated with food reward. Intra-accumbens amphetamine (20 micrograms) facilitated bar pressing for conditioned rewards. *Systemic administration of L-365,260 potentiated this amphetamine response but produced no effect on responding when administered alone. These findings suggest that endogenous CCKB mechanisms may normally inhibit DA function in reward-related behaviors.*





> Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion.
> Higgins GA, Sills TL, Tomkins DM, Sellers EM, Vaccarino FJ.
> 
> Addiction Research Foundation, University of Toronto, Ontario, Canada.
> Recent evidence shows that rats exhibit individual differences in their locomotor response to amphetamine (AMP). Moreover, evidence has accumulated showing that high-AMP responders exhibit more mesolimbic dopaminergic (DAergic) activation in response to AMP treatment than low-AMP responders. Cholecystokinin (CCK) is a peptide that is colocalised with mesolimbic DA and exerts complex modulatory actions on DA function. Two CCK receptor subtypes have been identified and selective antagonists have been developed. To examine the possible contribution of endogenous CCK mechanisms to individual differences in responsivity to AMP treatment, male Wistar rats were divided into low- and high-AMP responders based on a median split of their locomotor response to AMP and the effects of the selective CCK antagonists L365-260 (CCKB; 0.01, 0.1, 0.5 mg/kg; n = 16) and devazepide (CCKA; 0.001, 0.01, 0.1 mg/kg; n = 23) were determined. *Results showed that L365-260 (0.1 mg/kg) potentiated AMP-induced hyperactivity in low-AMP responders but did not affect AMP-induced hyperactivity in high-AMP responders. Devazepide was without effect in both groups of animals. This pattern of results suggests that CCKB, but not CCKA, receptor mechanisms contribute to interindividual variation in responsivity to AMP.*





> Differences in behavioural effects of amphetamine and dopamine-related gene expression in wild-type and homozygous CCK2 receptor deficient mice.
> Rünkorg K, Värv S, Matsui T, Kõks S, Vasar E.
> 
> Department of Physiology, University of Tartu, Ravila 19, Tartu 50411, Estonia. [email protected]
> Neuropeptide cholecystokinin (CCK) interacts with dopamine in the regulation of motor activity and motivations. Therefore, in CCK(2) receptor deficient mice the behavioural effects of repeated amphetamine administration and changes in dopamine-related gene expression were studied. Four-day amphetamine (1 mg/kg) treatment induced a significantly stronger motor sensitization in homozygous mice compared to their wild-type littermates. However, in the conditioned place preference test the action of amphetamine was more pronounced in wild-type animals. As opposed to wild-type mice, amphetamine (1-3 mg/kg) did not cause a significant conditioned place preference in homozygous mice. The expression of Tyhy gene was elevated in the mesolimbic structures and Drd2 gene was down-regulated in the mesencephalon of saline-treated homozygous mice in comparison with respective wild-type group. Four-day treatment with amphetamine induced a significant increase in the expression of Tyhy in the mesencephalon, striatum and mesolimbic structures of wild-type mice, whereas in homozygous mice a similar change was evident only in the mesencephalon. Also, the expression of Drd1 gene in the striatum and Drd2 gene in the mesolimbic structures of wild-type mice were up-regulated under the influence of amphetamine. In conclusion, the present study established differences in the behavioural effects of amphetamine in wild-type and homozygous mice. The increased tone of dopaminergic projections from the mesencephalon to mesolimbic structures is probably related to increased amphetamine-induced motor sensitization in homozygous mice. The lack of development of up-regulation of Drd1 and Drd2 genes after repeated treatment with amphetamine probably explains the reduced place conditioning in CCK(2) receptor deficient mice.


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## crayzyMed (Nov 2, 2006)

> Effect of CCK1 and CCK2 receptor blockade on amphetamine-stimulated exploratory behavior and sensitization to amphetamine.
> Alttoa A, Harro J.
> 
> Department of Psychology, Center of Behavioral and Health Sciences, Tartu University, Tiigi 78, 50410 Tartu, Estonia.
> Interactions between dopaminergic neurotransmission and cholecystokinin (CCK) in the CNS may be important in the pathogenesis of psychotic disorders and substance abuse. In this study, the effect of coadministration of the selective CCK receptor antagonists devazepide and L-365,260 (for selectively blocking CCK1 and CCK2 receptors, respectively), on the effect of amphetamine on the rat exploratory behavior, and on sensitization of locomotor response to amphetamine, were studied. Amphetamine (0.5 mg/kg) increased exploratory activity in the exploration box for 5 consecutive testing days, while devazepide (10 microg/kg) blocked and L-365,260 (10 microg/kg) enhanced amphetamine-induced stimulation of activity. Devazepide coadministration prevented the development of sensitization to amphetamine, while coadministration of L-365,260 with amphetamine potentiated the locomotor effect of a challenge dose of amphetamine. *These results suggest that endogenous CCK, released during exploratory activity, shapes behavioral responses to amphetamine by acting on both receptor subtypes, and modulates the development of sensitization to amphetamine.*





> CCK2 receptor-deficient mice have increased sensitivity of dopamine D2 receptors.
> Kõks S, Abramov U, Veraksits A, Bourin M, Matsui T, Vasar E.
> 
> Department of Physiology, Biomedicum, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia. [email protected]
> The present study supports a role of CCK(2) receptors in the regulation of dopamine neurones. In pharmacological studies conducted on male CCK(2) receptor-deficient mice the changes in the activity of dopamine system were established. A low dose of dopamine agonist apomorphine (0.1 mg/kg), stimulating the pre-synaptic dopamine receptors, induced significantly stronger suppression of locomotor activity in mutant mice (-/-) compared to their wild-type littermates (+/+). The administration of amphetamine (3-6 mg/kg), a drug increasing dopamine release, caused a dose-dependent stimulation of locomotor activity in wild-type mice. In mice lacking CCK(2) receptors, a lower dose of amphetamine (3 mg/kg) tended to suppress the motor activity, whereas the higher dose (6 mg/kg) induced the significantly stronger motor stimulation in mutant mice. Moreover, in the CCK(2) receptor-deficient mice the affinity of dopamine D(2) receptors, but not 5-HT(2) receptors, was increased. *Altogether, the targeted genetic suppression of CCK(2) receptors increased the sensitivity of pre- and post-synaptic dopamine D(2) receptors.*


So it appears that CCKB antagonists potentiate amphetamines and that CCKB knockout mice have more sensitive dopamine receptors. Potential target for amphetamines tolerance?



> Targeted mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in female mice.
> Raud S, Rünkorg K, Veraksits A, Reimets A, Nelovkov A, Abramov U, Matsui T, Bourin M, Volke V, Kõks S, Vasar E.
> 
> Department of Physiology, Biomedicum, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
> RATIONALE: Evidence suggests that GABA and CCK have opposite roles in the regulation of anxiety. OBJECTIVE: The aim of the present work was to study diazepam-induced anxiolytic-like action and impairment of motor co-ordination, and the parameters of benzodiazepine receptors in mice lacking CCK2 receptors. METHODS: The action of diazepam (0.5-3 mg/kg i.p.) was studied in the elevated plus-maze model of anxiety and rotarod test using mice lacking CCK2 receptors. The parameters of benzodiazepine receptors were analysed using [3H]-flunitrazepam binding. RESULTS: In the plus-maze test, the exploratory activity of the homozygous (-/-) mice was significantly higher compared to their wild-type (+/+) littermates. However, the wild-type (+/+) mice displayed higher sensitivity to the anxiolytic-like action of diazepam. Even the lowest dose of diazepam (0.5 mg/kg) induced a significant increase of open arm entries in the wild-type (+/+) mice. A similar effect in the homozygous (-/-) mice was established after the administration of diazepam 1 mg/kg. The highest dose of diazepam (3 mg/kg) caused a prominent anxiolytic-like effect in the wild-type (+/+) mice, whereas in the homozygous (-/-) animals suppression of locomotor activity was evident. The performance of the homozygous (-/-) mice in the rotarod test did not differ from that of the wild-type (+/+) littermates. However, a difference between the wild-type (+/+) and homozygous (-/-) animals became evident after treatment with diazepam. Diazepam (0.5 and 3 mg/kg) induced significantly stronger impairment of motor co-ordination in the homozygous (-/-) mice compared to their wild-type (+/+) littermates. The density of benzodiazepine binding sites was increased in the cerebellum, but not in the cerebral cortex and hippocampus, of the homozygous (-/-) mice. CONCLUSIONS: Female mice lacking CCK2 receptors are less anxious than their wild-type (+/+) littermates. The reduced anxiety in homozygous (-/-) mice probably explains why the administration of a higher dose of diazepam is necessary to induce an anxiolytic-like action in these animals. The highest dose of diazepam (3 mg/kg) induced significantly stronger suppression of locomotor activity and impairment of motor co-ordination in the homozygous (-/-) mice compared to the wild-type (+/+) littermates. *The increase in the action of diazepam is probably related to the elevated density of benzodiazepine receptors in the cerebellum of homozygous (-/-) mice. The present study seems to be in favour of increased tone of the GABAergic system in mice without CCK2 receptors.*


Upregulation of benzodiazepines receptors too.

There's 1 CCK antagonist available called proglumide, its a CCKA - B antagonist wich has been shown to reverse opiate tolerance in mice, could it work for amphetamines too? The problem is that CCKA antagonism has a negative effect on amphetamines, but if CCKB antagonism actually upregulates dopamine receptors due to a feedback system we could use proglumide in high doses for a week after wich we enjoy the benefits.

Well it appears that proglumide actually reverses tolerance due to some kind of feedback system (atleast thats the impression i'm getting) so it should be possible to take it a few days to REVERSE amphetamine tolerance, so there basicly wont be a need to keep on taking the med, so tolerance to proglumide itself isnt an issue.

Co administration of proglumide wont work anyway because its also a CCK1 antagonist.

If memantine slows down tolerance enough so it takes maybe a month (?) before you get tolerance, we would only need a "proglumide reset break" once a month. It seems to appear that in case of amphetamine NMDA antagonists slow tolerance down rather then fully stop it, so i beleive there's some other mechanism on play too.

Or this may be some wishfull thinking, definatly warrants a few trials tough! .

Amphetamine releases both glutamate and CCK, both are known tolerance inducers, i'm thinking that CCK is the missing link for absolute tolerance prevention.

A goal i would NEED to achieve as i need amphetamine for its mood boosting anti social anxiety effects.


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## euphoria (Jan 21, 2009)

I'm pretty sure memantine prevents tolerance a lot longer than 1 month...


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## crayzyMed (Nov 2, 2006)

euphoria said:


> I'm pretty sure memantine prevents tolerance a lot longer than 1 month...


Yeah actually your right, ive been reading succes stories of more then 6 months, there's even one of 2 year on dr bob forum by a user called andrewB.

But i know 1 person that got tolerant to amphetamine after a few months of daily use, he's on 100mg of amphetamine a day tough so 20mg of memantine may have been too low for he's amphetamine dose, and ive read about other ppl needing atleast 30mg of memantine for good tolerance prevention so that could be he's 2 problems.
He didnt notice any tolerance/dependency to opiates/benzo's tough after months of daily use on he's memantine dose.

Considering that all other experiences are very positive about the use of NMDA antagonist for amp, i agree that they should work long term.

Still was interesting to theorize about another possible mechanism:b.


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## euphoria (Jan 21, 2009)

crayzyMed said:


> But i know 1 person that got tolerant to amphetamine after a few months of daily use, he's on 100mg of amphetamine a day tough so 20mg of memantine may have been too low for he's amphetamine dose, and ive read about other ppl needing atleast 30mg of memantine for good tolerance prevention so that could be he's 2 problems.
> He didnt notice any tolerance/dependency to opiates/benzo's tough after months of daily use on he's memantine dose.


Maybe the reason he got tolerant to amphetamine but not the others is neurotoxicity, with such a high dose. Perhaps supplements to prevent neurotoxicity, and/or a higher memantine dose, could have prevented it. I certainly wouldn't rely on just NMDA antagonists to sustain amphetamine effects, due to the neurotoxicity factor.


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## crayzyMed (Nov 2, 2006)

Neurotoxiticy only occurs when you inject 9 gram daily. And he also added in deprenyl wich helped to return the magic but that pooped out again too. And deprenyl prevents neurotoxiticy.

Anyway, its probably just he's memantine dose.


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## crayzyMed (Nov 2, 2006)

Bad news for benzo users:



> Dizocilpine does not prevent the development of tolerance to the anxiolytic effects of diazepam in rats.
> Fernandes C, File SE.
> 
> Psychopharmacology Research Unit, Neuroscience Research Centre, GKT School of Biomedical Sciences, King's College London, Hodgrin Building, Guy's Campus, London, SE1 9RT, UK.
> The non-competitive NMDA receptor antagonist, dizocilpine (0.25 mg/kg), has previously been shown to block the development of tolerance to the sedative effects of diazepam (2 mg/kg). Since there is considerable evidence that different mechanisms underlie the development of tolerance to the sedative and anxiolytic effects of diazepam, the present experiment examined whether dizocilpine would block the development of tolerance to diazepam's anxiolytic effects. Rats tested after an acute dose of diazepam (2 mg/kg) showed an anxiolytic effect, measured by an increase in the time spent in social interaction, whereas those tested after 21 days of treatment had scores equal to the control group. This development of tolerance was not blocked by concomitant administration of dizocilpine (0.25 mg/kg). Thus, these results provide further evidence that the mechanism underlying tolerance to the anxiolytic effects of diazepam is different from that underlying tolerance to the sedative effects. Copyright 1999 Published by Elsevier Science B.V.


Well, NMDA antagonists are still usefull with benzo's as they inhibit dependency wich is the biggest issue with benzo's.

I wonder how it is possible to only prevent tolerance to the sedative effects?

Anyway, NMDA antagonists do appear to inhibit tolerance to the good effects of opiates and amphetamines and as i personally dont use benzo's i dont really care:b.

Would CCK be the missing link here?


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## crayzyMed (Nov 2, 2006)

> Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat
> 
> G Micheletti, B Lannes, C Haby, E Borrelli, E Kempf, JM Warter, J Zwiller
> 
> ...





> Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.
> Author: Mele, A : Cabib, S : Oliverio, A
> Citation: Psychopharmacology-(Berl). 1995 Feb; 117(3): 313-7
> Abstract: The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.


I suppose this means that postsynaptic receptors are upregulated and that NMDA antagonism prevents the upregulation of presynaptic receptors induced by stress?



> Summary. Behavioral changes have previously been reported following administrations of uncompetitive NMDA receptor antagonists memantine, amantadine and MK-801 for 14 days, at the doses that produce plasma levels comparable to those seen in patients (20, 100 and 0.31 mg/kg/day respectively). Using the same doses, the effect on receptor binding (autoradiography) was studied in rats. [3H]MK-801 binding was increased in the dentate gyrus and CA3 region of the hippocampus (35.2 and 24.3% respectively) following 3 days S.C. infusion of memantine by ALZET minipumps. One daily injection of memantine for 14 days, increased [3H]MK-801 binding in the frontal cortex by 40.3%. *The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%*. None of these treatments changed the expression of muscarinic receptors. It is concluded that subchronic blockade of the NMDA receptor by uncompetitive antagonists at moderate (therapeutically-relevant) doses induced only minor changes in NMDA and dopamine D2 receptor expression.





> Decreased striatal dopamine-receptor binding in sporadic ALS: Glutamate hyperactivity?
> 
> O. J. M. Vogels, MD, PhD, W. J. G. Oyen, MD, PhD, B. G. M. van Engelen, MD, PhD, G. W. A. M. Padberg, MD, PhD and M. W. I. M. Horstink, MD, PhD
> From the Departments of Neurology (Drs. Vogels, van Engelen, Padberg, and Horstink) and Nuclear Medicine (Dr. Oyen), University Hospital Nijmegen, the Netherlands.
> ...





> Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
> Rogóz Z, Dlaboga D, Dziedzicka-Wasylewska M.
> 
> Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. [email protected]
> In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptors, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either drug alone given. Since it has been suggested that dopamine receptors, among others, may play a role in anti-immobility effect of IMI, in the present study we examined the effect of AMA (10 mg/kg) and IMI (5 and 10 mg/kg) given separately or jointly, as a single dose or repeatedly (twice daily for 14 days) on the dopamine D2 and D3 receptors in the rat brain, using receptor autoradiography. Following repeated administration of AMA alone or given in combination with IMI (5 mg/kg), the binding of [3H]quinpirole (dopamine D2/D3 receptors agonist) was increased, and similar changes were observed at the level of mRNA encoding dopamine D2 receptors. We used [3H]7-OH-DPAT to selectively label the dopamine D3 receptors. This experiment has shown that AMA given repeatedly did not induce statistically significant changes in the D3 receptor binding, while IMI at both used doses, increased the [3H]7-OH-DPAT binding, and this effect was still observed after repeated joint administration of AMA with both doses of IMI. However, using both radioligands, we did not observe any synergistic or even additive effects in the binding studies after joint administration of AMA and IMI. Nevertheless, *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, *and this effect may explain their synergistic action observed in the behavioral studies involving dopaminergic transmission.


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## crayzyMed (Nov 2, 2006)

Ketamine doesnt seem to increase D2 density.
Edit: i misread the study as "ketamine does not increase D2 density".


> Psychopharmacology (Berl). 2002 Dec;164(4):401-6. Epub 2002 Oct 12.
> Ketamine does not decrease striatal dopamine D2 receptor binding in man.
> Aalto S, Hirvonen J, Kajander J, Scheinin H, Någren K, Vilkman H, Gustafsson L, Syvälahti E, Hietala J.
> 
> ...


Study about the developping brain, can be ignored.


> Pharmacol Biochem Behav. 2003 Mar;74(4):943-52.
> Effects of postnatal PCP treatment on locomotor behavior and striatal D2 receptor.
> Sircar R, Soliman KF.
> 
> ...





> Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
> Nair VD, Savelli JE, Mishra RK.
> 
> Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
> The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. I*n the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP.* The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors.





> J Mol Neurosci. 1998 Oct;11(2):121-6.
> Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
> Nair VD, Savelli JE, Mishra RK.
> 
> ...


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## crayzyMed (Nov 2, 2006)

Anyway, high D2 sensivity is what we want as all drugs of abuse downregulate D2 receptors (tolerance).


> Am J Psychiatry. 2008 Apr;165(4):507-14. Epub 2008 Mar 3.
> Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse.
> Fehr C, Yakushev I, Hohmann N, Buchholz HG, Landvogt C, Deckers H, Eberhardt A, Kläger M, Smolka MN, Scheurich A, Dielentheis T, Schmidt LG, Rösch F, Bartenstein P, Gründer G, Schreckenberger M.
> 
> ...


Since that NMDA antagonism appears to upregulate D2 receptors, memantine hasnt only potential to prevent tolerance from happening, it could actually reverse it too.


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## euphoria (Jan 21, 2009)

So drugs could cause tolerance by increased NMDA receptor activity, opposite to the effect of NMDA antagonists. So much evidence now that NMDA antagonists prevent tolerance.

By the way crayzyMed, are you getting that memantine from a doctor or self prescribed? I forgot.


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## crayzyMed (Nov 2, 2006)

Lol we are cross posting, its answered in my other thread.

Yes it does appear that NMDA downregulates D2 receptors, it seems that NMDA antagonist dont just prevent downregulation to all kinds of receptors, its an interaction between the NMDA and dopamine system.
This further supports the use of NMDA antagonists for tolerance prevention.


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## crayzyMed (Nov 2, 2006)

Besides, i have just received a PM of someone on another board that has succesfully used memantine for amphetamine tolerance for a period of 19 months, he's on 40mg a day.


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## euphoria (Jan 21, 2009)

crayzyMed said:


> it seems that NMDA antagonist dont just prevent downregulation to all kinds of receptors, its an interaction between the NMDA and dopamine system.


But I thought NMDA antagonists also prevent ethanol and benzo tolerance?


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## crayzyMed (Nov 2, 2006)

euphoria said:


> But I thought NMDA antagonists also prevent ethanol and benzo tolerance?


Yeah your correct, opioid, gaba and other receptors need to be involved too or it wont be capable of fully preventing tolerance for those substances, i tought of this after i made that post.
I assumed that because it prevents D2 downregulation, the main reward receptors it decreases tolerance to all substances, but there's more involved (sedation, analgesia etc). And those receptors need to be sensitive too.


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## crayzyMed (Nov 2, 2006)

Glutamate involved in antidepressant withdrawal? say whaat.


> Titre du document / Document title
> NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress, GABA levels and NMDA receptor binding in rat hippocampus
> Auteur(s) / Author(s)
> HARVEY Brian H. ; JONKER Lucy P. ; BRAND Linda ; HEENOP Marietha ; STEIN Dan J. ;
> ...





> Abstract
> 
> Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term morbidity during treatment of depression. Increasing evidence supports an association between depressive illness and disturbances in brain glutamate activity, nitric oxide synthesis, and γ-amino butyric acid. Animal models also confirm that suppression of glutamate N-methyl-D-aspartate receptor activity or inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of γ-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide. These stress-induced structural changes can be reversed by antidepressant treatment. In patients with depression, antidepressant withdrawal after chronic administration is associated with a stress response as well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal evokes a behavioral stress response that is associated with increased hippocampal N-methyl-D-aspartate receptor density, with both responses dependent on N-methyl-D-aspartate receptor activation. Drawing from both clinical and preclinical studies, this article proposes a preliminary molecular perspective and hypothesis on the neuronal implications of adherence to and discontinuation of antidepressant medication.


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## crayzyMed (Nov 2, 2006)

More good news.


> *Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT1A serotonin receptors in the rat brain*
> 
> K. Wdzony*, M. Ma
> 
> ...


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## zodiac55 (Mar 12, 2010)

*scribble scribble* duly noted.


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## The Professor (Jul 31, 2011)

euphoria said:


> Magnesium probably wouldn't be strong enough alone (in normal doses), but it'd augment the neuroprotective effect of DXM etc..
> 
> DXM polistirex would give a slow release of DXM, and avoid the bromine in HBr.


I never would have guessed DXM is neuroprotective. Does is mean it is actually _healthy_ to take DXM? (low dose I'm assuming)


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## crayzyMed (Nov 2, 2006)

The Professor said:


> I never would have guessed DXM is neuroprotective. Does is mean it is actually _healthy_ to take DXM? (low dose I'm assuming)


No it means its neuroprotective under certain conditions, kinda like a coat protects against the cold weater, but without cold weater wearing a caot is pretty useless.


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## jonny neurotic (Jan 20, 2011)

I am considering a stack of DXM, sulpiride(low dose) and caffeine with the occasional ethylphenidate(very low dose intranasally) for focus. DXM has opioid activity which will be good for SA and depression. Perhaps a DXM memantine combo would be better...


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## boostinggtir (May 27, 2011)

good read


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