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    NMDA antagonists for tolerance, a collection of the evidence and anecdotal reports 
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    Bluelighter MeDieViL's Avatar
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    I tought id make this thread for those interested in using NMDA antagonists for drug tolerance.


    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.

    NMDAR and stimulant tolerance: (unfortionally i found references regarding sensitisation, it is established however that NMDA antagonists upregulate several dopamine receptors backed up by many members that used it succesfull for stim 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-na´ve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole.

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

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

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

    NMDA antagonists and serotonin

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

    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

    -more mentally stimulating and less physically stimulating

    -greatly reduced negative side effects(rapid pulse, rebound effect after dosage wears off) and condition of user less obvious to the outside world

    -x-ray vision

    i wish.

    anyway, overall i am very pleased with the results of the combination. i plan on adding calcium and magnesium to my regimine as well.
    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.
    Around this time dose started to increase to an extra 15 mg since i had the extra bottle...
    Then came getting invited to my friends djing at a club and other clubbing events
    I don't drink, smoke weed, or do any other drugs anymore, only other drug I use is clonazepam, and I WILL NOT abuse that, I've seen where benzo abuse takes you, and not going back there...that is merely something for longstanding insomnia and social anxiety (pre-existing to ADD diagnosis)
    Started popping 60 mg IR
    Started doing 60 on and off on regular days...but not all at once like on the club nights
    eventually every other weekend or every weekend id do 90mg in one sitting
    started to lose its effect...so I started blowing 60....
    I got an extra 10mg IR added to my 30mg xr script
    as finals approached, just to get basically baseline i needed 60mg, and to get focused or motivated it took 90. Ended up doing about 240 mg over two days (spread out doses)
    but I never quite as focused as I used to be. never felt high at all.

    Once finals were over, I saw where this was going, decided to say **** this **** I'm not wasting my script, my mental energy, and being depending on unreasonable amounts of amphetamine just to function, not even get the therapeutic effect.

    abstained from usage for 5 days completely, took tyrosine, choline, nootropics, brain supplements, etc.

    Today I decided, just to see how it goes, to take 30mg, less than my full prescribed dose, along with a tablespoon of delsym and some magnesium.

    Not only did I get the euphoria and motivation, but I also got the focus and energy and I DIDN'T FOR ONCE end up with freezing cold fingers!!! and its lasted much longer than using 4 times as much has and im not crashing.

    Personally, I think that along with vitamins and supplements to restore neurotransmitters, taking a few day breaks between using as well as using dxm and magnesium with your dosage can change the outcome of your entire experience.

    one thing i've considered...while using adderall daily, i also used nootropics....
    they counteract the nmda effects magnesium and dxm have i think..atleast the racetams.
    i didnt use any today..
    could aniracetam/other racetams possibly increase tolerance while using them?
    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
    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.
    all the people i know who heavily abused dissociatives are now off them and are some of the most intelligent people i know.
    olneys is OUT THE ****ING WINDOW come one now people. if wedMD calls DXM a "Co-Analgesic", well **** thats good enough for me. it also greatly reduces fybromyalgia pain even by itself, and if i take grapefruit juice first then a small dose of dex when i have NO pain meds, it actualy gives me SIGNIFICANT wd relief AND pain relief.
    look more into these drugs before you bash them anyone, please, because i believe them to be miracle drugs.
    and ketamine, is the safest of the dissociateves anyways, just for your information. even when all that olneys **** was going around, they said PCP was most likely to cause it, followed by dxm, followeed by ketamine. i have also have ++++ psy experiences on K.
    show me any real evidence that the **** is hard on the brain any ill listen. but even if it is miniscualy bad for you............its either that, or a never ending skyrocketing opiate tolerance.............hummmm.....hard descision
    peace
    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.

    I've waited to log this post because I was hoping to learn exactly what mechanisms allowed memantine to work this way. But, at this point, at least, I will have to say that it is a bit of a mystery. Presumable, amphetamine induces hyperglutaminergic activity, which incuces the tolerance, which the memantne is able to prevent by limiting glutaminergic activity to within physiologically safe bounds.

    Also memantine is seemingly effective for tardive dyskinsia (see patent referred to above). Also effective as a adjunct mood stabilizer to valporate acid (sp?) and possibly lamotrigine.
    It is speculated to be effective for OCD disorders. Also I can't help but wonder if it won't prevent , at least in some , instances, of AD poop out.

    BTW: I take, 5mg/day selegiline, 40mg/day adderall, 30mg./day memantine, 4g.day klonopin at night and 50mg./day of amisulpride.

    AndrewB
    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 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
    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.
    Last edited by MeDieViL; 21-11-2010 at 20:19.
     

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    Bluelighter Mr Blonde's Avatar
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    Good work collating everything brother, interesting reading there.
     

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    Couple more anecdotal bits from myself:
    Quote Originally Posted by monstanoodle
    Quote Originally Posted by DexterMeth
    Quote Originally Posted by monstanoodle
    I've heard many-a-time about NMDA Antagonists acting to diminish tolerance to Opiates and, I'm in no way certain that it's a complete fact, but one week I was using both H(eroin) and K(etamine) together - smoking the prior, snorting the latter.
    I did notice that after a week of heavy use of both that, when I had run out of H, used K for a few more days (which helped massively with any withdrawals I experienced) until I scored some more H, my tolerance to H was practically the same as it was at the beginning of the week if not reduced slightly.

    Now, I'm not claiming it to be a solution to tolerance, and I could even be mistaken, but it definitely seemed to have the effect of keeping tolerance at a constant level and then, when only using K for a couple of days, had slightly diminished my Opiate tolerance.

    Anyway, it may be something you (dear reader) might wish to try out and report back. Just thought I'd add my tuppence
    But you stopped doing H in the first place for a few days before starting again. How does this prove anything other than taking a break from opiates for enough time to get the shit out of your body will lower your tolerance?
    After a few days my tolerance would have definitely remained the same (from past experience) and my tolerance, after using K simultaneously, was the same as it was at the beginning of the week of using both H & K.
     

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    Bluelighter MeDieViL's Avatar
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    Interesting thx for posting your experience, altough i have to say that its possible that ketamine isnt as effective as the other nmda antagonists due to its short half life, when it wears off there could also be a small rebound wich would be counterproductive. But it did seem to help you.

    Also a couple of extra notes:
    - Memantine is probably the best agent for tolerance to therapeutic doses of amp/opiates etc, but maybe not to recreational doses of a combination of several agents, this is because it has a VERY low affinity for the NMDA receptors, this way it can even be considered a cognitive enhancing drug as it doesnt interfere with normal cognition in most cases. However this also means that it can be easily overpowered if taking too high doses or combo's of several drugs.

    When going on a drug binge it would be better to use more powerfull NMDA antagonists like DXM (or augment memantine with some DXM).

    - When using DXM go for the extended release version to make sure it doesnt wear off too soon.
     

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    #5
    Quote Originally Posted by MeDieViL View Post
    Interesting thx for posting your experience, altough i have to say that its possible that ketamine isnt as effective as the other nmda antagonists due to its short half life, when it wears off there could also be a small rebound wich would be counterproductive. But it did seem to help you.
    Yes I can imagine that it's not the best NMDA Antagonist, but I think I know the reason as to why it may have worked so well...

    Basically I'm not one of those people who likes to snort half a G and fall into that strange ol' K-hole, I prefer to take small lines continuously.
    So, eventually I will meet the K-hole, but I build up to it slowly - little line by little line by little line.

    This will have kept the blood concentration more constant no doubt

    The Memantine does sound really good and would likely be perfect for the job
     

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    #6
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    You missed the most obvious one of all - NMDA antagonists effect on the tolerance of NMDA antagonists - has to be the most ridiculous of any drug. Someone came round with a bit of ket last night - been a bit of a drought on so had none for many months - tolerance has barely dropped in all that time. On the plus side, maybe it's kept my tolerance to other stuff down to more managing levels too
     

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    Quote Originally Posted by Shambles View Post
    You missed the most obvious one of all - NMDA antagonists effect on the tolerance of NMDA antagonists - has to be the most ridiculous of any drug. Someone came round with a bit of ket last night - been a bit of a drought on so had none for many months - tolerance has barely dropped in all that time. On the plus side, maybe it's kept my tolerance to other stuff down to more managing levels too
    Yes, ket tolerance is something unsolvable at this point, a drug i luckily never build a tolerance too but ive had so little oppertunities to try it.
     

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    Post has been updated, if anyone has more ref's regarding the interaction between NMDA and other receptors, please post them.
     

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    #9
    At the request of the OP, here's my purely ancedotal experience, the pharmacology is largely over my head. Having read that the use of DXM (among other which I do not have easy access to) could prevent tolerance to amphetamines I decided to give it a try. I had spent about a week with my anti-drug family, so I had used no drugs except a few benzos and a little pot. So my amphetamine tolerance was pretty low by my standards, though probably still off the charts compared to most people. I had easy access to but high quality ice and to anny meth [snip]. Obviously I can't give specific numbers for the purity of either, and I wasn't weighing my dose. I would just throw a large amount in a spoon and put an amount of water on it which was not sufficient to dissolve all the meth. I would then draw up a shot of what I assume to be the maximum amount of meth which will dissolve in that amount of water. If anyone knows how much meth say a CC of water will dissolve I'd be curious to know. Anyway, I would draw up 30 units per shot. This was a very strong dose, even with my tolerance. I was taking 60 mgs of DXM in the form of 4 15 mg robotussin cough gels twice a day, though I'm sure I missed a few doses given how spun I was. I would do a shot about every six hours, although I wasn't timing them or anything. This continued for what I later realized was 12 days. I neither upped my dose nor increased the number of doses per day. I've stay up this long on more occasions than I care to admit, and I would typically be up to around 50 units every 4 hours or so. Yes, I realize how insane these doses must seem. But even at the end (when my wife told me it was time to get some sleep) I had noticed no increase in tolerance. Also I had no paranoia at all, not even the level which would have been rational for someone in my position. I haven't had a chance to try this again, my lifestyle has changed to the point that more than a weeekend warrior type tweeking isn't an option. But I know myself well enough to know that I will go on another crazy meth run again, and when I do I absolutely will be repeating the DXM dosing, both for the sake of science and to get higher off my dope.

    This being a harm reduction site I feel obliged to say "Don't try this at home, these stunts are performed by experienced tweekers".
    Last edited by leftwing; 31-10-2010 at 10:06. Reason: incriminating stuff
     

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    #10
    ^just be a little more cautious posting such things in the future. law enforcement check these boards remember?
     

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    #11
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    Well, articles are articles, research is research... But to be honest I've never experienced a substantial decrease in opioid tolerance if any at all in my life. I've never been an every day consumer of any NMDA antagonist, I really did such things occasionally but it didn't really have any impact on my intake of opioids (well, unless I shot morphine and ketamine together - well, but I'd rather say it was kind of synergy between two drugs and not any decrease in tolerance).
     

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    Quote Originally Posted by adder View Post
    Well, articles are articles, research is research... But to be honest I've never experienced a substantial decrease in opioid tolerance if any at all in my life. I've never been an every day consumer of any NMDA antagonist, I really did such things occasionally but it didn't really have any impact on my intake of opioids (well, unless I shot morphine and ketamine together - well, but I'd rather say it was kind of synergy between two drugs and not any decrease in tolerance).
    Well thats kinda expected since NMDA antagonists wont reverse tolerance, they rather slow the development of tolerance, also you need to chronically dose them while you are taking the other drugs.

    DXM and memantine appear to work and we have good indications on what doses are effective, ketamine on the other hand has a very short half life wich could render it useless for this purpose, unless you really try to redose in time and do it chronically but thats rather impractical with ket.
     

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    Bluelighter MeDieViL's Avatar
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    Can anyone move my thread to the advanced section?

    Thx
     

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    Quote Originally Posted by MeDieViL View Post
    Can anyone move my thread to the advanced section?

    Thx
    I'll talk it over with the other Other Drugs moderators and see if they are on board with the idea. I don't see any problem with doing so though.

    I have always been impressed with your thread here, though I haven't had any practical purposes for it.

    Quote Originally Posted by MeDieViL View Post
    Post has been updated, if anyone has more ref's regarding the interaction between NMDA and other receptors, please post them.
    I have combined ketamine once with mushrooms (peak of the trip), and once with LSD (tail end of the trip). Both times I IV'd it. By far the effects lasted much longer than they otherwise would have (IV Ketamine by itself doesn't last long, but with the mushrooms, it lasted hours, seemingly much longer). During the tail end of the LSD trip, the duration was only 2-3x longer, but it was really, really intense, and definitely brought back a lot of the visual/tactile sensations that were waning.

    I was definitely impressed with both experiences and wasn't experiencing the high degree of synergy that I did.
     

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    The reason i wanted it in advanced is because i can get some more scientific discussions going, the thread is dropping to the back all the time anyway, perhaps its a better idea to make a link to my thread in one of the informative sticky's on here with general info about drug use.

    Cheers,

    I also have experimented with MDMA the last 2 weeks and memantine helps a ton with the comedown, basicly no week aftereffects, just a bit skecthed out the day after.
     

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    #16
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    I wonder how NMDA antagonism would affect benzo withdrawal... Its largely speculated that the vast majority of benzo withdrawals are mediated through NMDA getting out of control... I've heard of people K-holing themselves for literally days at a time and making it through benzo withdrawal...

    Unfortunately, getting ahold of memantine is proving difficult recently - I've been trying unsuccessfully for about a month now - because I would like to get off my benzos and anything that will help... but I'm not gonna shove myself in a permanent K-hole for a week.
     

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    #17
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    Quote Originally Posted by MagickalKat777 View Post
    I wonder how NMDA antonism would affect benzo withdrawal... Its largely speculated that the vast majority of benzo withdrawals are mediated through NMDA getting out of control... I've heard of people K-holing themselves for literally days at a time and making it through benzo withdrawal...
    Well, i good friend of me reversed allmost all the tolerance he had to xanax (took it for years) however that only happened when he went to 40mg of memantine, after that he added in topiramate and did a fast withdrawal (topiramate also blocks one of the pathways involved in withdrawal.
     

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    #18
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    Interesting... I'm on 40mg of valium a day and looking to get off as soon as possible - or at least knock the tolerance down to a point where I can taper much quicker...

    It seems that NMDA antagonism is the way to go... but getting the memantine is the problem. (I edited that initial post).

    And really, adding dope-a-max? Ugh.
     

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    #19
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    Here is he's experience:
    I took Alprazolam for 3 years, then went through accidental cold-turkey withdrawal because the local pharmacies weren't carrying any (happens where I live occasionally, sucky country/city). I experienced severe withdrawal symptoms including paranoia and transient psychosis but soon I got again on Alprazolam and thankfully didn't have a seizure. During that period I was completely tolerant to 2 mg Alprazolam's both sedative and anxiolytic effects.

    Since I started taking Memantine, the tolerance was reversed somewhat and 1 mg was anxiolytic and practical enough for social anxiety disorder. 2 mg was very effective sedative. Tolerance didn't develop any further from this point on.

    When I began tapering off Alprazolam for good, I was on 2 mg/day and the withdrawal was pretty negligible, only symptoms were irritability and slight sense of panicking, despite the rapid taper process.
    I remember him saying on MSN he added in topiramate to make the last taper easier wich worked succefully, the was off them quite quikcly.
     

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    Quote Originally Posted by Captain.Heroin View Post
    I'll talk it over with the other Other Drugs moderators and see if they are on board with the idea. I don't see any problem with doing so though.

    I have always been impressed with your thread here, though I haven't had any practical purposes for it.



    I have combined ketamine once with mushrooms (peak of the trip), and once with LSD (tail end of the trip). Both times I IV'd it. By far the effects lasted much longer than they otherwise would have (IV Ketamine by itself doesn't last long, but with the mushrooms, it lasted hours, seemingly much longer). During the tail end of the LSD trip, the duration was only 2-3x longer, but it was really, really intense, and definitely brought back a lot of the visual/tactile sensations that were waning.

    I was definitely impressed with both experiences and wasn't experiencing the high degree of synergy that I did.
    I'm still trying to figure out how they modulate the serotonine symptons, they appear to upregulate 5HT1A rapidly but no idea about the other receptors.
     

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    #21
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    Bump! I would like to get a few things discussed in the advanced section
     

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    #22
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    I've got 240 pills of "Namenda" (memantine) on the way... going to start with 10mg for 2 days to see how the brain fog is, then bump it to 20mg for a week - I have a feeling that is all that I'm going to need. Then when my valium suddenly knocks me on my ass I'm going to drop the dose by 10mg and see how I feel... if I'm still getting knocked out after a few days, I'm going to drop it again - by 5mg this time... even a 15mg cut in 2 weeks would make me supremely happy.

    I can do DXM too - it seems like people are using 60mg of Delsym? Would this be favorable as well? Or just do ONE NMDA antagonist? lol. I really want off of these fucking benzos!
     

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    #23
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    Well my mate only noticed a reversal of benzo tolerance after he went up to 30-40mg of memantine, you can augment mem with some DXM to get the same results of a lower dose.
     

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    #24
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    Well I started Delsym today. 30mg every 12 hours I imagine?
     

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    #25
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    Updating. I ended up taking 60mg Delsym at 2PM yesterday, 60mg at 4:30AM or so this morning.

    I ended up passing out some time around midnight and didn't take my valium. Upon waking at 4:30 I would normally be in mild withdrawal (half-life means nothing with my body - my metabolism is ridiculously fast) but I actually wasn't and I didn't take any valium until about 30 minutes ago when I took 10mg instead of my usual 20mg.

    My morning cigarette really hit me hard too. Like I smoked half of it and when I went back in the house, I was quite dizzy and had a huge nicotine rush but ironically I didn't have my heart rate start pounding like it normally would if I had such a rush.

    The NMDA antagonism is already starting to work its magic. The valium is kicking in faster and I've actually got some euphoria creeping in from it and its making me tired. This is astonishing - I've never gotten euphoria from any benzo except Xanax before - and I only got that when I first started to take it. The valium at half the dose is making me want to take a nap - and I just woke up - there really is a lot more than placebo to this!
     

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