55 replies to this topic

[medievil]

NMDA antagonists for drug tolerance, does it work? A collection of the evidence and anecdotal reports.

Ive posted this at a few other forums but id tought it make a thread here too for those interested.

Also i'm still working on the dopamine and serotonin section, the interactions between NMDA and several receptors specifically (NMDA and 5HT2C for example and the other individual receptors). So id appreciate any contributions .


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:

(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.
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 .

Edited by chrono, 09 September 2010 - 10:53 PM.
updated from below

[medievil]

[quote]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.[/quote]
[quote]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.[/quote]
[quote]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.[/quote]
[quote]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[/quote]
And more....

[quote]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.[/quote]
[quote]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[/quote]
[quote]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.[/quote]
[quote]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.[/quote]
[quote]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![/quote]

[quote]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[/quote]
[quote]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.[/quote]

[quote]> 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.[/quote]

[quote]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?[/quote]

[quote]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[/quote]

[quote]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.[/quote]

[OneScrewLoose]

What I would like to know is if it prevent un-tolerance as well. As in, if you quit a drug, and you are on a NDMA antagonist, does your body go back to normal, or stay in the withdrawal state?

[medievil]

What I would like to know is if it prevent un-tolerance as well. As in, if you quit a drug, and you are on a NDMA antagonist, does your body go back to normal, or stay in the withdrawal state?

Anecdotally, memantine seems to reverse tolerance faster then a break without memantine, only a few days will do what otherwise would take alot longer.

Edited by medievil, 15 May 2010 - 05:35 PM.

[KimberCT]

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

[medievil]

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

Thats good to hear, i have a friend who said that memantine significantly reduced the crashes of he's amp medication.

[medievil]

If a mod could replace the reference section at the first post with this one id appreciate it .

<snip>

Edited by chrono, 09 September 2010 - 10:57 PM.
Done! (2010-09-09)

[chrono]

Great review, medievil. Forgot to contribute to it. Here's a few papers showing the specific effectiveness of memantine (and a few others) in preventing/reversing opioid tolerance:

Effects of NMDA receptor channel blockers, dizocilpine and memantine, on the development of opiate analgesic tolerance induced by repeated morphine exposures or social defeats in mice.
Belozertseva IV, Bespalov AYu.
Laboratory of Behavioral Pharmacology, Institute of Pharmacology

Separate groups of mice were exposed to repeated social confrontations or injections of morphine with each defeat or morphine injection followed by administration of either dizocilpine (0.03-0.3 mg/kg, i.p.) or low-affinity channel blocker memantine (3-30 mg/kg, i.p.). Both dizocilpine and memantine were effective in preventing the development of repeated morphine-induced tolerance to acute morphine analgesia. Treatments with NMDA receptor antagonists that retarded development of non-associative tolerance also suppressed the establishment of associative tolerance significantly. Social defeat-induced tolerance was prevented by dizocilpine but not by memantine.

PMID: 9750014 [PubMed - indexed for MEDLINE]

Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test.
Popik P, Kozela E.
Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences

...Male Albino Swiss mice were tested for analgesia using the tail-flick apparatus. Preliminary experiment was designed to find out the optimal dose of morphine and the number of injections that would produce tolerance to its analgesic effects...Memantine pretreatment (5 and 10 mg/kg, but not 2.5 mg/kg), given 30 min prior to each morphine dose during the development of tolerance period, inhibited the rightward shift of morphine cumulative dose-response curve. Thus, pretreatment with memantine at doses of 2.5, 5 and 10 mg/kg resulted in ED50 values of 12.13, 4.74 and 1.95 mg/kg, respectively, corresponding to 3.35, 1.02 and 0.94 fold changes. These data indicate that low affinity, clinically available NMDA receptor antagonist, memantine, may be used to inhibit the development of morphine tolerance.

PMID: 10600036 [PubMed - indexed for MEDLINE]

This abstract appears to suggest that memantine inhibits the acute analgesis effects of morphine, which raises a question about its utility in treating opioid tolerance (though I haven't seen this mentioned elsewhere):

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice.
Popik P, Kozela E, Danysz W.
Institute of Pharmacology, Polish Academy of Sciences

Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance...Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

PMID: 10763858 [PubMed - indexed for MEDLINE]

Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice.
Kozela E, Pilc A, Popik P.
Institute of Pharmacology, Polish Academy of Sciences

Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. RESULTS: MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception.

PMID: 12442203 [PubMed - indexed for MEDLINE]

[someidiot]

Just for a head's up (i know, not really topic related, but i didn't think such warranted a new thread):

J Alzheimers Dis. 2010;20(2):607-15.
Folic Acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer's disease transgenic model.
Chen TF, Huang RF, Lin SE, Lu JF, Tang MC, Chiu MJ.

Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Abstract
Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-beta (Abeta) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Abeta accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies in the Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)_M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)_M (both p < 0.05). Analysis of Abeta40 and Abeta42 showed lower brain loads in both treatment groups but this did not reach statistical significance. Histopathology analysis showed that Tg(+)_M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)_M (p< 0.005). DNA analysis revealed that in the Tg(+)M_+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)_M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Abeta production, and modification of brain gene expression.

Edited by someidiot, 21 September 2010 - 11:24 PM.

[medievil]

I would also like to add that the anecdotal reports give a too positive view, some ppl did end up getting tolerance altough alot slower then normal, memantine isnt a magic cure, but for best succes its adviced to:

Go to 40mg of memantine a day
Take occasional breaks, like a 2 day break every week from the meds your taking, or a 4 day break once and awhile.

My personal experience with it is so far limited, i take AMT, amphetamine and a benzo for my social anxiety, well see how good memantine will prevent tolerance, ive also just taken a 4 day break from my meds wich i will do on a regular basis.

So far it completely halted my nicotine tolerance, but i havent been using it long term yet, altough my previous experience with it was bad as the benefits quickly turned into irritability.

It does significantly reduce the anxiety and crashes from amp.

Edited by medievil, 21 September 2010 - 11:47 PM.

[someidiot]

Studies on wakefulness-promoting effect of memantine in rats Original Research Article
Behavioural Brain Research, Volume 206, Issue 2, 20 January 2010, Pages 274-278
Takayuki Ishida, Yoshihito Obara, Chiaki Kamei

We hypothesized that memantine, an anti-dementia drug, may be useful for the treatment of excessive daytime sleepiness. The effect of memantine on excessive sleepiness after 6 h sleep deprivation was studied in comparison with that of methylphenidate, and the involvement of the dopaminergic system in the wakefulness-promoting effect of memantine was also evaluated. Electrodes for electroencephalogram (EEG) and electromyogram (EMG) were chronically implanted into the cortex and dorsal neck muscle, respectively, of adult male rats. EEG and EMG were recorded with an electroencephalograph for 6 h (19:00–01:00). After sleep deprivation (13:00–19:00), compensatory excessive sleepiness (19:00–01:00) was observed in rats. Memantine (10 mg/kg, p.o.) and methylphenidate (10–30 mg/kg, p.o.) caused a significant increase of sleep latency compared with the control group. Furthermore, a significant increase in total awake time and significant decreases in total non-rapid eye movement (NREM) sleep and REM sleep times were observed by administration of memantine (3–10 mg/kg) and methylphenidate (3–30 mg/kg) compared with control in sleep deprivation rats. Although the effect of memantine was significantly suppressed by D1 receptor antagonist SCH 23390 (0.1 mg/kg, i.p.), D2 receptor antagonist raclopride had no antagonistic effect (1 mg/kg, i.p.). From these results, the effect of memantine on sleepiness after sleep deprivation was similar to that of methylphenidate, and D1 receptor may be involved in the effect of memantine.

...I'm still looking for substantial research evidencing memantine to be someone nootropic...as I am not using it for amp tolerance.

Edited by someidiot, 22 September 2010 - 11:14 PM.

[medievil]

Well i dont really think memantine is a nootropic, i see it more as a "corrector agent".

[someidiot]

Well i dont really think memantine is a nootropic, i see it more as a "corrector agent".

thanks. i just can't seem to get over this study (and other studies citing neurogenesis):

Memantine: The Next Trend in Academic Performance Enhancement?
KEN S. OTA, OMS III; TINA GODWIN, OMS II

(which has already been posted by another user)

[medievil]

Well i dont really think memantine is a nootropic, i see it more as a "corrector agent".

thanks. i just can't seem to get over this study (and other studies citing neurogenesis):

Memantine: The Next Trend in Academic Performance Enhancement?
KEN S. OTA, OMS III; TINA GODWIN, OMS II

(which has already been posted by another user)

That article is just theoretical, i have my strong doubts about memantine being cognitive enhancing, the autor just talks about certain things memantine induces but lets not forget NMDA plays a major role in cognition, if memantine changes cognition it will be cognitive decline (but i beleive its minimal).

[someidiot]

(which has already been posted by another user)

That article is just theoretical, i have my strong doubts about memantine being cognitive enhancing, the autor just talks about certain things memantine induces but lets not forget NMDA plays a major role in cognition, if memantine changes cognition it will be cognitive decline (but i beleive its minimal).

so the 'upregulation' retoric is BS?

Edited by chrono, 26 September 2010 - 01:55 PM.
fixed quote tag

[medievil]

so the 'upregulation' retoric is BS?

What upregulation are you talking about? (long time since ive read the article) sure memantine probably upregulates several things that are neurotrophic or are connected to one individuals IQ, but we also have the NMDA antagonism wich generally causes cognitive decline.

[someidiot]

i'm extrapolating...nevermind. Thanks...

[medievil]

Ive just looked at the article:

Moreover, a direct relationship has been observed between NAA levels in the brain and intelligence. Healthy individuals with high levels of NAA appear to have higher scores on intelligence tests than healthy individuals with lower levels of this marker in brain tissue.12 It may be possible that the higher levels of NAA indicate an increased presence of neuronal processes and their synapses.

While this is probably true, we also have the nmda antagonism wich can cause cognitive decline, so the net effect of all factors combined can have a negative effect on cognition.

[someidiot]

I have a limited knowledge of neurochemistry, so...
You can google the article title below and read the whole study if you wish. (if you haven't already)

Memantine Improves Spatial Learning in a Transgenic Mouse Model of Alzheimer's Disease
Rimante Minkeviciene, Pradeep Banerjee and Heikki Tanila
+ Author Affiliations

Department of Neuroscience and Neurology, University of Kuopio, Finland (R.M., H.T.); Forest Research Institute, Jersey City, New Jersey (P.B.); and Department of Neurology, Kuopio University Hospital, Kuopio, Finland (H.T.)
Address correspondence to:
Dr. Heikki Tanila, Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland. E-mail: heikki.tanila@uku.f

[medievil]

Well alzheimer is a condition wich damages cognition, memantine helps the symptons and thus improves cognition in alzheimer patients, this is of little relevance to normal healthy subjects.

[someidiot]

"Several NMDA receptor antagonists possessing high affinity for NMDA receptors [e.g., (+)MK-801] have been found to cause neurobehavioral adverse effects such as hallucination and cognitive impairment (Benvenga and Spaulding, 1988; Abi-Saab et al., 1998). These adverse events have largely limited the clinical development of high-affinity NMDA receptor antagonists. An alternative approach to avoid such side effects is to produce a partial rather than complete blockade of the NMDA receptor."

...extrapolating that one can reap benefits (theorized in the first article mentioned) without a terrible risk of 'cognitive decline'

...i keep staring at my ADC cart, wondering to buy or not to buy lol... I guess it would be good for my daytime sleepiness...ha!

[medievil]

Well, cognitive decline with memantine is very minimal and its a very clean benign med.

I highly recommened it.

[someidiot]

once again, thank you.

[Willou]

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

[medievil]

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

Yeah all it takes is a small break and tolerance reverses rapidly, also on memantine i dont notice any withdrawal on the days i dont take my stuff, just feel baseline, it also prevents amp crashes in my experience.

[Happy Gringo]

Hi guys,
I must admit that I got a bit confused after reading the studies. At times, it seemed that the memantine was blocking the effect of the opioids. At other times it was suggested that NMDA antagonists be co-administered with opioids.
So will memantine basically reset opioid tolerance to some extent? My wife has chronic back pain and needs codeine to function on a daily basis, but must take more and more as time goes on. I suspect this is from tolerance. Would trying to take a break from it for a day and taking maybe 40 mg. of memantine possibly have a positive effect?


Thanks.

[medievil]

Hi guys,
I must admit that I got a bit confused after reading the studies. At times, it seemed that the memantine was blocking the effect of the opioids. At other times it was suggested that NMDA antagonists be co-administered with opioids.
So will memantine basically reset opioid tolerance to some extent? My wife has chronic back pain and needs codeine to function on a daily basis, but must take more and more as time goes on. I suspect this is from tolerance. Would trying to take a break from it for a day and taking maybe 40 mg. of memantine possibly have a positive effect?


Thanks.

Its definatly worth a try, NMDA antagonist should slow or block tolerance to the analgesic effects of opioids. Wheter they reverse it i dont know, there's one anecdotal experience that suggests it does:

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

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

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

http://www.mindandmuscle.net/forum/index.php?showtopic=16611&st=0&p=236973&hl=+opiate%20+tolerance%20+memantine&fromsearch=1&#entry236973

There's also potential in curcumin:

To quote from the study:

Quote
[Morphine tolerance] was completely reversed by curcumin, an inhibitor of CREB-binding protein histone acetyltransferase activity. As the daily injection of curcumin completely reversed the morphine tolerance, this epigenetic control seems to be related to a BDNF-mediated counterbalance effect to reduce morphine analgesia.


This occurred at doses from 10-100 mg/kg p.o. in mice, which is fairly realistic and comparable to human doses that we've discussed. As the mechanism was via CREB, this should in theory apply to tolerance for any drugs of addiction. However altering CREB activity in the brainstem is going to alter analgesic tolerance without changing reward/NAc tolerance; this study did not assess whether CREB activity was changed in the NAc. If it was, then yes, curcumin should reverse amphetamine tolreance too, at least to some extent.

But no, there are no studies that have directly looked at this.

ex dubio's post in this thread:
http://www.mindandmu...pic=41876&st=90

[medievil]

There also seems to be potential in quercetine:

Titre du document / Document title
Quercetin, a bioflavonoid, reverses development of tolerance and dependence to morphine
Auteur(s) / Author(s)
SINGH Amanpreet (1) ; NAIDU Pattipati S. (1) ; KULKARNI Shrinivas K. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, INDE
Résumé / Abstract
Quercetin, a bioflavonoid (25 and 50 mg/kg), when chronically administered for 9 days, failed to produce any significant change in tail flick latency as compared to control mice. However, repeated administration of quercetin (25 and 50 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). Quercetin (25 and 50 mg/kg) also suppressed naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 in morphine-tolerant mice. Pretreatment of mice with quercetin (10-50, ip) significantly reversed the morphine (5 mg/kg)-induced delay in gastric transit, whereas a higher dose of quercetin (100 mg/kg) did not have any significant effect on morphine-induced delay in gastric transit. Quercetin per se had no effect on gastric transit. In conclusion, the results of the present study suggest potential use of quercetin in alleviating the adverse effects of opioid treatment.

Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence

Authors: Pattipati Naidu a; Amanpreet Singh a; Dipesh Joshi a; Shrinivas Kulkarni a
Affiliation: a Pharmacology Division, University Institute of Pharmaceutical Sciences Panjab University Chandigarh India.
DOI: 10.1080/13556210310001602248
Publication Frequency: 4 issues per year
Published in: Addiction Biology, Volume 8, Issue 3 September 2003 , pages 327 - 336
Subject: Addiction & Treatment;
Formats available: PDF (English)
The circumstances under which this title is published have changed:

Reason for change: Changed Publisher
Now published by: Wiley-Blackwell Publishing
Date of change: 2006
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View Article: View Article (PDF)


Abstract
In an earlier study, we reported the ability of quercetin to reverse the development of morphine tolerance and dependence in mice. In the present study we have attempted to explore the possible involvement of nitric oxide (NO) system in quercetin reversal of morphine tolerance and dependence in mice. Co-administration of L-NG-nitro arginine methyl ester (L-NAME) or quercetin with morphine during the induction phase (days 1 - 9) delayed the development of tolerance to the antinociceptive action of morphine and also reversed naloxone precipitated withdrawal jumps. L-Arginine administration during the induction phase enhanced the development of tolerance to the antinociceptive effect of morphine but had no effect on the naloxone-precipitated withdrawal jumps. During the expression phase (day 10) acute administration of quercetin or L-NAME reversed, whereas L-arginine facilitated naloxone- precipitated withdrawal jumps in morphine-tolerant mice, but none of these drugs affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of quercetin or L-NAME with L-arginine during the induction phase antagonized the latter effects on the development of morphine tolerance. Also, prior administration of quercetin or L-NAME reversed the L-arginine potentiation of naloxone-precipitated withdrawal jumps in morphine-tolerant mice. The results of the present study suggest that quercetin reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity.

So there's a few things to try.

[chrono]

Amantadine is an NMDA channel blocker similar to memantine; doses (100-200mg?) and brain concentrations (6-21μM [1]) are much higher than memantine. It inhibits nAChR response with an IC50 of 6uM [2], which is at the bottom end of the clinically relevant range. Without knowing exactly how nicotinic desensitization factors into enhancement of cognition, it's hard to say how detrimental this might be (see here).


Studies showing modulation of tolerance, including one on humans!:

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

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

PMID: 8208762 [PubMed - indexed for MEDLINE]

Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study.
Snijdelaar DG, Koren G, Katz J.
Acute Pain Research Unit, Toronto General Hospital

BACKGROUND: Amantadine is known to be a noncompetitive N-methyl-D-aspartate receptor antagonist and may be useful in preventing postoperative central sensitization, acute opioid tolerance, and opioid-induced hyperalgesia, thereby decreasing pain and analgesic requirements. The aim of this pilot study was to evaluate the effects of perioperative oral amantadine on postoperative pain and analgesic consumption. METHODS: Twenty-four patients scheduled to undergo radical prostatectomy were given oral amantadine before and after surgery in a randomized, double-blind, placebo-controlled manner. After surgery, patients received intravenous patient-controlled analgesia with morphine for 48 h. Wound pain intensity, sensitivity to mechanical pressure around the surgical wound, and incidence of bladder spasm pain were assessed. Blood samples were drawn for analysis of amantadine, morphine, and the morphine metabolites. Adverse effects and patient satisfaction were assessed. RESULTS: The cumulative morphine consumption was significantly lower in the amantadine group at all time points (except at 48 h), amounting to a 32% reduction over the 48-h period. Forty-eight hours after surgery, visual analog pain scores to pressure applied near the wound were significantly lower in the amantadine group than in the placebo group. In addition, the number of patients reporting bladder spasm pain was significantly lower in the amantadine group. Plasma concentration of morphine-3-glucuronide was significantly lower at the end of surgery in the amantadine group. Pharmacokinetic analyses showed that the plasma clearance of morphine at 22-24 h after surgery was also significantly lower in the amantadine group. CONCLUSION: The results suggest that perioperative oral amantadine reduces postoperative opioid consumption by pharmacokinetic mechanisms, although additional pharmacodynamic interactions may also be involved.

PMID: 14695734 [PubMed - indexed for MEDLINE]

Also, moved this to nootropics, since on reflection I think the applicability is mainly to modulating the mental effects of agents (at least the ones we discuss here).

Edited by chrono, 28 September 2010 - 06:51 PM.

[medievil]

Interesting study's, thx for posting those!