Memantine Protects Against MDMA and Amphetamine Neurotoxicity

[Taal]

At least to a certain extent.



Came across these on another forum in case you all havn't seen them. I'm sure you all know of/heard about Memantine's neuroprotective effects, but these three Spanish studies in rats highlight some specific neuroprotective properties that I was quite excited to read about/further verify. I wanted to share them.



I wish I knew the exact dosages they used or had the full texts.



http://www.ncbi.nlm.nih.gov/pubmed?term=18582864

Eur J Pharmacol. 2008 Jul 28;589(1-3):132-9. Epub 2008 May 20.

Memantine prevents the cognitive impairment induced by 3,4-methylenedioxymethamphetamine in rats.

Camarasa J, Marimón JM, Rodrigo T, Escubedo E, Pubill D.



Laboratory of Pharmacology and Pharmacognosy, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain. jcamarasa@ub.edu <jcamarasa@ub.edu>



Abstract



Amphetamine abuse is an important risk factor for the development of cognitive impairment involving learning and memory. Since in previous studies we have demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by amphetamine derivatives, the present paper seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both nicotinic and NMDA receptors) counteracts the memory impairment induced by 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) administration in male Long Evans rats. In mice, MDMA and MEM induced a locomotor stimulant response but with a different profile. Moreover, MEM inhibited the rearing and thygmotaxis behaviour induced by MDMA. Non-spatial memory was tested in the object recognition test and the spatial learning and memory was tested in the Morris water maze. In our experimental conditions, rats receiving MEM pre-treatment recovered the ability to discriminate between the familiar and the novel object that had been abolished by MDMA treatment. Animals treated with MDMA showed impaired learning in the Morris water maze. Results of the probe trial demonstrated that MDMA-treated rats did not remember the location of the platform, but this memory impairment was also prevented by the MEM pre-treatment. Moreover, MEM alone improved the learning task. No differences were observed between the different groups as regards swim speed. In conclusion, MEM significantly improved the learning and memory impairment induced by MDMA and constitutes the first approach to the treatment of the long-term cognitive deficits found in ecstasy users.

PMID: 18582864 [PubMed - indexed for MEDLINE]

Edit: Just realized the experiment's conclusion in this was somewhat premature. They in the conclusion:

treatment of the long-term cognitive deficits

Not sure how they can conclude this would be a treatment for people who have used ecstasy many times in the past and experienced a cognitive deficit when they pre-treated the mice with Memantine before they ever even gave them MDMA.



They do, however, note that MEM did improve cognitive function alone, but that really shouldn't matter whether or not the user took MDMA many times in the past....unless (and this involves alot of Ex Dubio and mine's discussion way down below and some potential theories floating around the net about Memantine they are suggesting in the full text (which I have not read yet) that the cognitive deficit is due to a structural change in the alpha 7 nAChR such as downregulation or desensitization; if so, then perhaps Memantine's alpha 7 nAChR antagonism could fix or upregulate these receptors back to baseline levels and fix the cognitive deficit. However, I doubt they are suggesting this. And even then, its a somewhat unproven theory.



The Memantine could block some of the desired user effects of MDMA if co-administered with it although we don't know which ones in rats would translate into humans or how they would exactly.



Nonethless they do say that "MDMA and MEM induced a locomotor stimulant response but with a different profile" suggesting that the effects of MDMA were somehow changed or some of them were blocked/blunted. Additionally, Memantine has some stimulating effects of it's own due to its effected receptor profile and some of its specific potential dopamine receptor agonism (and the behavior has simply just been observed with rats treated with MEM alone). The abstract doesn't say what behaviors were observed in the MEM alone group; the full text may although I havn't had time to read it.



http://www.ncbi.nlm.nih.gov/pubmed?term=18455739

Neuropharmacology. 2008 Jun;54(8):1254-63. Epub 2008 Apr 9.

Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.

Chipana C, Torres I, Camarasa J, Pubill D, Escubedo E.



Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda Joan XXIII s/n, Zona Universitaria Pedralbes, 08028 Barcelona, Spain.

Abstract

We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.



PMID: 18455739 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17980434

Neurotoxicology. 2008 Jan;29(1):179-83. Epub 2007 Sep 22.

Memantine prevents MDMA-induced neurotoxicity.



Chipana C, Camarasa J, Pubill D, Escubedo E.



Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.

Abstract



MDMA (ecstasy) is an illicit drug causing long-term neurotoxicity. Previous studies demonstrated the interaction of MDMA with alpha-7 nicotinic acetylcholine receptor (nAChR) in mouse brain membranes and the involvement of alpha-7 nicotinic acetylcholine receptors (nAChR) in dopaminergic neurotoxicity induced by MDMA in mice. The aim of the present study was to investigate the utility of memantine (MEM), an alpha-7 nAChR antagonist used for treatment of Alzheimer's disease patients, to prevent neurotoxicity induced by MDMA in rats and the oxidative effect of this amphetamine derivative in mice striatal synaptosomes. In isolated mouse striatal synaptosomes (an in vitro model of MDMA neurotoxicity of dopaminergic origin), MDMA (50 microM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 microM). This effect of MEM was fully prevented by PNU 282987 (0.5 microM), a specific agonist of alpha-7 nAChR. The preventive effect of MEM on this oxidative effect can be attributed to a direct antagonism between MDMA (acting probably as agonist) and MEM (acting as antagonist) at the alpha-7 nAChR. In Dark Agouti rats (an in vivo model of MDMA neurotoxicity of serotonergic origin), a single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment. [(3)H]Paroxetine binding (a marker of serotonergic injury) was measured in the hippocampus of animals killed at 24h and 7 days after treatment. MDMA induced a significant reduction in [(3)H]paroxetine binding sites at both times of sacrifice that was fully prevented by pre-treatment with MEM. Since previous studies demonstrate that increased glutamate activity is not involved in the neurotoxic action of MDMA, it can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR, although an indirect mechanism based on the interplay among the various neurotransmission systems leading to an increase in basal acetylcholine release should also be taken into account.



PMID: 17980434 [PubMed - indexed for MEDLINE]

Wonder if the neuroprotective effect of Memantine blocks some of the beneficial affects of these drugs though. Personally, I have found on at least one or two occasions that taking 20mg Memantine about an hour before taking 40mg Adderall IR does tend to blunt the effects somewhat, although they are still noticeable; however, take into account that this was not a very controlled observation by me as I don't feel I have had enough experience combining these two medications.



I do remember Medieval saying something about that though.







Edit: (yes this is repeating what I said in at post way below) Got full text of these now. Have not read through them yet. If anyone else would like help in getting them, PM me. I may be able to provide some assistance

[kassem23]

Wonder if the neuroprotective effect of Memantine blocks some of the beneficial affects of these drugs though. Personally, I have found on at least one or two occasions that taking 20mg Memantine about an hour before taking 40mg Adderall IR does tend to blunt the effects somewhat, although they are still noticeable; however, take into account that this was not a very controlled observation by me as I don't feel I have had enough experience combining these two medications.

You should note that taking Memantine, acutely, and chronically is vastly different. Acutely Memantine actually messes with my cognition, and many others I believe, causing brain-fog, memory-problems and perhaps some degree of depersonalization/derealization.



Chronically, Memantine enhances my cognition, whereas for others it does not. Acutely, Memantine antagonizes alpha7 nicotinic receptors, which is believed to be the mechanism by which Memantine gives brain-fog and/or memory-problems. We do not know, however, yet, whether the up-regulation due to chronic antagonism yields cognitive enhancement or impairment, or neither for that matter.



It can be proposed -- on that basis -- that Memantine may interfere with baseline cognition by other means, most likely through the NMDA antagonism, perhaps because of low baseline glutamergic signalling.. I'm not sure.



In conclusion, if you'd like, try to take 20 mg Memantine -- with no amphetamine -- for about a week, and notice the brain-fog slowly diminishing. When you feel ready, try the 40 mg IR Adderall that you are prescribed, and the experience should resemble that of the initial phase of amphetamine treatment.

[Taal]

After writing this, I realized it was a ..excessively.. large, especially for a reply. In fact, it's been split up into 4 different posts. Perhaps I should of made a new topic. The length of this post has nothing to do with an amphetamine induced writing problem that I am trying to deal with.

You should note that taking Memantine, acutely, and chronically is vastly different. Acutely Memantine actually messes with my cognition, and many others I believe, causing brain-fog, memory-problems and perhaps some degree of depersonalization/derealization.



Chronically, Memantine enhances my cognition, whereas for others it does not. Acutely, Memantine antagonizes alpha7 nicotinic receptors, which is believed to be the mechanism by which Memantine gives brain-fog and/or memory-problems. We do not know, however, yet, whether the up-regulation due to chronic antagonism yields cognitive enhancement or impairment, or neither for that matter.



It can be proposed -- on that basis -- that Memantine may interfere with baseline cognition by other means, most likely through the NMDA antagonism, perhaps because of low baseline glutamergic signalling.. I'm not sure.



In conclusion, if you'd like, try to take 20 mg Memantine -- with no amphetamine -- for about a week, and notice the brain-fog slowly diminishing. When you feel ready, try the 40 mg IR Adderall that you are prescribed, and the experience should resemble that of the initial phase of amphetamine treatment.

Thanks for your help. I'm trying to stick with the Memantine but it does seem to have a few other side effects too. The more I learn about the more questions I have. Perhaps you or others could lend more of your knowledge to me:



1) I found that Memantine has this very strange effect on sleep for me. Usually, when going natural, I sleep for quite a while 8-10 hours, but tend to have moderate trouble getting up in the morning. If I drink heavily before going to sleep, then I only sleep for about 5 hours then wake up and can't get back to sleep. I will feel slightly sleep deprived and "out of it" then. I have heard/read that alcohol can disrupt sleep architecture. Additionally, a similar phenonmenon happens when taking stimulants that are affecting me when I go to sleep like caffeine or amphetamine. It especially happened when I used to take AMP (that old energy product). I'd wake up not really feeling like I need more sleep and not being able to get back to sleep; but, I would still feel a bit "out of it" like I'm lacking something in my brain. It's hard to put into words. It does make sense, though...stimulants would also disrupt sleep architecture.



Now, with Memantine a similar phenomenon is happening to me. I will sleep (usually for exactly 7.5 - 8 hours) and then just wake up not being able to get back to sleep. I feel better than I do when I attempt to sleep with alcohol or stimulants, but something is still "off". I feel like I didn't get something that I needed during sleep. The feeling is definitely separate from the brain fog; although, it may be contributing in a very small way.



Sometimes I take diphenhydramine or doxylamine succinate. These have always made me sleep for about 10-12 hours and wake up at something like 2 or 3 o'clock when only taking 25mg of one of those (never combined them). It would be extremely difficult to get up, and I'd feel quite groggy. Now, even if I take 50mg of diphenhydramine and 50mg doxylamine, I wake up 8 hours later and feel exactly the same as if I hadn't taken either. Normally, having that sort of dose would put me out for a WHILE and I'd feel preeettty horrible.



Also, since taking it, amphetamine withdrawal was completely abolished. Normally, if I took amph with a high frequency and moderately high quantity , about 2 days after the last dose I would feel extremely lazy, flat mooded, and not motivated to do anything at all.



Have you or anyone else experienced effects like these? I read alot of reports saying that they would end up sleeping for a very long time or being drowsy a large part of the day.



I theorize that these would mostly be attributable to Memantine's D2 agonism, but I'm not sure. Correct me if you believe otherwise. D2 agonism property is cited from Wikipedia which cites:

Seeman P, Caruso C, Lasaga M (February 2008). "Memantine agonist action at dopamine D2High receptors". Synapse 62 (2): 149–53. doi:10.1002/syn.20472. PMID 18000814.



Reason I'm worried about this is because I have personally realized as well as read from others that getting the proper quantity, quality, type, and phases of sleep is a huge factor in how effect amphetamine is at its desired effects.



I also came across a few studies in regards to Memantine. It definitely does something to sleep.

Ross Fiziol Zh Im I M Sechenova. 2009 Aug;95(8):802-12.

[Effects of memantine on convulsive reactions and sleep-waking cycle in Krushinskiĭ-Molodkina strain rats with the inherited predisposition to audiogenic convulsions].



Vataev SI, Zhabko EP, Lukomskaia NIa, Oganesian GA, Magazanik LG.

Article in Russian



Krushinskii-Molodkina strain rats have an inherited predisposition to audiogenic convulsions and are used as a natural animal model in the anticonvulsive drugs studies. We have investigated whether changes in the glutamatergic synaptic transmission are involved in the mechanism of audiogenic convulsions and functional organization of sleep-waking cycle observed in rats of this line. For this purpose Memantine, a selective uncompetitive blocker of NMDA receptors was used. Memantine was injected i.m. at the dose 5 or 10 mg/kg injected 30 min, 1, 2 or 3 hours before the sound stimulus (the sine-wave tone 8 kHz, 90 db). We evaluated the latent period of initial enhanced motor activity, the appearance and intensity of clonic seizures, and thereafter the tonic seizures accompanied by extension of limbs and tail. The maximal attenuation of convulsive attack to the level of initial motor excitement only was occurred in 60% of rats between 1 and 2 hours after memantine pretreatment. No difference between the doses 5 and 10 mg/kg was observed. The effect of memantine began to decrease when memantine was injected 3 h before convulsion provocation. The recording of EEG by chronically implanted electrodes was performed from the rats of Krushinsky-Molodkina line for the study of memantine effects on the sleep organization. The sleep of these rats during the first hour after 5 or 7 mg/kg memantine injection exhibited as the short periods of slow-wave sleep only which disappeared completely thereafter 54.4 +/- 4.9 and 39.9 +/- 5.2 min correspondingly. The complete sleep loss was observed approximately 2-2.5 hours later and followed by appearance of episodes of slow-wave sleep. The first episodes of fast-wave sleep occurred 3-4 hours later. Their reappearance evidenced of the completion of memantine action on the somnogenic brain systems and the beginning of recovery of normal sleep-waking organization. Thus the manifestations of unidirectional and synchronous memantine action on audiogenic seizures and disturbances of sleep-waking mechanisms may speak about involvement of NMDA receptors in both of epileptogenesis and somnogenic system of Krushinsky-Molodkina rats line.

Behav Brain Res. 2010 Jan 20;206(2):274-8. Epub 2009 Sep 23.

Studies on wakefulness-promoting effect of memantine in rats.



Ishida T, Obara Y, Kamei C.



Department of Medicinal Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Kita-Ku, 700-8530, Okayama, Japan.



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.

Side note: Interestingly in this study, Memantine was found to be a D1 agonist and found not to be a D2 agonist. This contradicts that first study I cited up top from wikipedia that say it IS a D2 agonist. Strange. All the japanese people I know were smart in school, so they were probably correct on this one

Jk, I like russians too...

Int J Geriatr Psychiatry. 2010 Oct;25(10):1030-8.

The effect of memantine on sleep behaviour in dementia with Lewy bodies and Parkinson's disease dementia.



Larsson V, Aarsland D, Ballard C, Minthon L, Londos E.



Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Sweden. v.larsson@ucl.ac.uk

Abstract



OBJECTIVE: Two common and characteristic sleep disturbances have been described in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD); excessive daytime sleepiness and REM sleep behaviour disorder (RBD). This study is an analysis of a secondary outcome measure of a larger study already reported, aimed to determine whether memantine has an effect on the sleep disturbances in DLB and PDD patients.



METHODS: Patients with DLB or PDD were included in a placebo-controlled, randomised controlled study of memantine (20 mg per day) for 24 weeks. The Stavanger Sleep Questionnaire and the Epworth Sleepiness Scale were used to evaluate the effect on sleep disturbances.



RESULTS: Forty two patients started treatment; 20 with memantine and 22 with placebo. The primary analysis was the comparison of change between the two groups during a 24-week period, using the modified ITT population (last observation carried forward). At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened. Mean difference between the groups (0.5 [0.05-0.90]) was significant (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness.



CONCLUSIONS: Memantine decreases probable REM sleep behaviour disorder in patients with DLB and PDD. Both diagnostic groups contributed equally to the outcome.

There's more studies on pubmed about this, but I'll spare you. Looks like Memantine messed with non-rapid and rapid eye movement sleep cycles in the Japanese study with rats, effected sleep cycles (I believe negatively, but not sure) in the Russian study in rats, and helped sleep in humans with Parkinson's and Lewy bodies disease in the Swedish study that were effected by "probably REM sleep behavior disorder".

[Taal]

2)

In conclusion, if you'd like, try to take 20 mg Memantine -- with no amphetamine -- for about a week, and notice the brain-fog slowly diminishing. When you feel ready, try the 40 mg IR Adderall that you are prescribed, and the experience should resemble that of the initial phase of amphetamine treatment.

I'm curious as to why you all are exactly suggesting to not take amphetamines but instead take a week or more off while slowly increasing in dose and allowing brain fog to alleviate (theoretically waiting for the alpha-7 nicotinic receptors to upregulate). There are a few strange things around this:



-People around the net and various forums all seem to be doing something different, recommending something different, and reporting various results with this. For instance, some guy over at the addforums is reporting just starting out on 10mg a day and that that is having tremendous effects the alleviation of his tolerance to his specific desired effects of amphetamines. I realize effects from drugs do vary from person to person.

Chronically, Memantine enhances my cognition, whereas for others it does not. Acutely, Memantine antagonizes alpha7 nicotinic receptors, which is believed to be the mechanism by which Memantine gives brain-fog and/or memory-problems. We do not know, however, yet, whether the up-regulation due to chronic antagonism yields cognitive enhancement or impairment, or neither for that matter



It can be proposed -- on that basis -- that Memantine may interfere with baseline cognition by other means, most likely through the NMDA antagonism, perhaps because of low baseline glutamergic signalling.. I'm not sure.

-I believe the general consensus is the brain fog is contributed to the alpha 7 nicotinic receptor antagonism (assuming these are separate from the NMDA antagonism and I'm not corrected). At least, that's what alot of people seem to have posted. I know on wikipedia, it says that with a citation:



Wiki:

It can be noted that memantine is an antagonist at alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment.

Citations:

1)Mol Pharmacol. 1998 Mar;53(3):555-63. "Open-channel blockers at the human alpha4beta2 neuronal nicotinic" acetylcholine receptor. Buisson B, Bertrand D. Department of Physiology, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland.

2)Buisson B, Bertrand D (1 March 1998). "Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor". Mol Pharmacol. 53 (3): 555–63. PMID 9495824. http://molpharm.aspetjournals.org/cg...g&pmid=9495824.

3)Aracava Y, Pereira EF, Maelicke A, Albuquerque EX (March 2005). "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 312 (3): 1195–205. doi:10.1124/jpet.104.077172. PMID 15522999.



Upon further investigation, I could only find reasoning that the alpha 7 nAChR antagonism was responsible for the initial brain fog in citation #3 from wikipedia:

"It is suggested that blockade of alpha7 nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well."



Citations #1 and #2 just seemed to say it was an alpha7 nicotinic receptor antagonist. I believe they were referencing previous sentences in the article.



I'm not sure about the NMDA antagonism interfering with cognition as there are other substances that have NMDA antagonist properties that do not seem to interfere with cognition such as Huperzine A (some citations about its NMDA antagonism later) or simply magnesium. However, perhaps Memantine's antagonism works in a different way or on different specific receptors within the NMDA subcategory such as "low baseline glutamergic signalling" like you said and this accounts for or has an additive effect to its initial cognitive decline; It is a "selective NMDA antagonist" according to wiki however accurate and relevant that may be.



Lets say the brain fog has nothing to do with Memantine's NMDA antagonist properties for a bit (as you said yourself, you're not sure either):



If Memantine's non-competitive NMDA antagonist activity is what we're looking for, then isn't that generally completely separate from its alpha-7 nicotinic receptor antagonism or am I wrong here. I mean, sure, we're waiting for those receptors to upregulate so that we get the theoretical and anecdotally noted cognitive enhancement from it, but, theoretically, that shouldn't have much to do with amphetamine's receptor profile or effects. Right? So then why abstain from amphetamine use while starting Memantine?



Side note: After doing a bit of searching last night on this I found some REALLY interesting studies that seem to highlight a property/mechanism of amphetamine that I do not believe has been mentioned at any forums before (or at least I hope not otherwise I'll look retarded) and has huge relevance to Memantine's ability to lower amphetamine tolerance. I'll talk about these soon.







Also, although Memantine is definately a good candidate for the NMDA antagonism job, I'm curious as to why it is the NMDA antagonist of choice? I know one of the reasons is because of its low side effect and interaction properties in comparison to some other NMDA antagonists such as ketamine, PCP, or DXM (already tried that one...not so good). However, noone (anywhere) seems to have tried any of the other such as Acamprostate or even Huperzine A, which after doing a bit of research, seems to put up quite a fight against Memantine and is much easier to get. Acamprostate is simply taurine that is able to cross the blood brain barrier, generally I'd say has a low side effect and contraindication profile, is available to get if you're able to get Memantine, and has the added bonus of being used to treat alcholism...but noone seems to be using it except for one guy I read about here on M&M. Although, I havn't done the research on it, I suspect that Acamprostate would not affect sleeping cycles or quality.



Anyways, here is some info about Huperzine A:

J Appl Toxicol. 2001 Dec;21 Suppl 1:S47-51.

The NMDA receptor ion channel: a site for binding of Huperzine A.



Gordon RK, Nigam SV, Weitz JA, Dave JR, Doctor BP, Ved HS.



Division of Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. Richard.Gordon@na.amedd.army.mil



Huperzine A (HUP-A), first isolated from the Chinese club moss Huperzia serrata, is a potent, reversible and selective inhibitor of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE) (Life Sci. 54: 991-997). Because HUP-A has been shown to penetrate the blood-brain barrier, is more stable than the carbamates used as pretreatments for organophosphate poisoning (OP) and the HUP-A:AChE complex has a longer half-life than other prophylactic sequestering agents, HUP-A has been proposed as a pretreatment drug for nerve agent toxicity by protecting AChE from irreversible OP-induced phosphonylation. More recently (NeuroReport 8: 963-968), pretreatment of embryonic neuronal cultures with HUP-A reduced glutamate-induced cell death and also decreased glutamate-induced calcium mobilization. These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-D-aspartate (NMDA) glutamate subtype receptor is found. We have now investigated the interaction of HUP-A with glutamate receptors. Freshly frozen cortex or synaptic plasma membranes were used, providing 60-90% specific radioligand binding. Huperzine A (< or =100 microM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist). In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo K(i) approximately 6 microM. Furthermore, when neuronal cultures were pretreated with HUP-A for 45 min prior to NMDA exposure, HUP-A dose-dependently inhibited the NMDA-induced toxicity. Although HUP-A has been implicated to interact with cholinergic receptors, it was without effect at 100 microM on muscarinic (measured by inhibition of [3H]QNB or [3H]NMS binding) or nicotinic [3H]epibatidine binding) receptors; also, HUP-A did not perturb adenosine receptor binding [3H]PIA or [3H]NECA). Therefore, HUP-A most likely attenuates excitatory amino acid toxicity by blocking the NMDA ion channel and subsequent Ca2+ mobilization at or near the PCP and MK-801 ligand sites. Thus, on the one hand, HUP-A could be used as a pretreatment against OPs and it might also be a valuable therapeutic intervention in a variety of acute and chronic disorders by protecting against overstimulation of the excitatory amino acid pathway. By blocking NMDA ion channels without psychotomimetic side-effects, HUP-A may protect against diverse neurodegenerative states observed during ischemia or Alzheimer's disease.

Neurosignals. 2005;14(1-2):71-82.

Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer's disease.



Wang R, Tang XC.



State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai, China.



Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer's disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.

Chem Biol Interact. 2008 Sep 25;175(1-3):387-95. Epub 2008 May 23.

[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats.



Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP.



Department of Biochemical Pharmacology/Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.



The toxicity of organophosphorous (OP) nerve agents is attributed to their irreversible inhibition of acetylcholinesterase (AChE), which leads to excessive accumulation of acetylcholine (ACh) and is followed by the release of excitatory amino acids (EAA). EAAs sustain seizure activity and induce neuropathology due to over-stimulation of N-methyl-d-aspartate (NMDA) receptors. Huperzine A (Hup A), a blood-brain barrier permeable selective reversible inhibitor of AChE, has been shown to reduce EAA-induced cell death by interfering with glutamate receptor-gated ion channels in primary neuronal cultures. Although [-]-Hup A, the natural isomer, inhibits AChE approximately 38-fold more potently than [+]-Hup A, both [-]- and [+]-Hup A block the NMDA channel similarly. Here, we evaluated the protective efficacy of [+]-Hup A for NMDA-induced seizure in a rat model. Rats implanted with radiotelemetry probes to record electroencephalography (EEG), electrocardiography (ECG), body temperature, and physical activity were administered various doses of [+]-Hup A (intramuscularly) and treated with 20 microg/kg NMDA (intracerebroventricular) 20-30 min later. For post-exposure, rats were treated with [+]-Hup A (3 mg/kg, intramuscularly) 1 min after NMDA (20 microg/kg). Our data showed that pre- and post-exposure, [+]-Hup A (3 mg/kg) protects animals against NMDA-induced seizures. Also, NMDA-administered animals showed increased survival following [+]-Hup A treatment. [+]-Hup A has no visible effect on EEG, heart-rate, body temperature, or physical activity, indicating a reduced risk of side effects, toxicity, or associated pathology. Our results suggest that [+]-Hup A protects against seizure and status epilepticus (SE) by blocking NMDA-induced excitotoxicity in vivo. We propose that [+]-Hup A, or a unique combination of [+]- and [-]-Hup A, may prove to be effective for pre- and post-exposure treatment of lethal doses of OP-induced neurotoxicity.

If you are looking for NMDA antagonism, neuroprotection, improvement in cognitive function, and low risk of side effects, huperzine A puts up quite a fight against Memantine.



Like I said before though, later on I found some evidence that Memantine could actually be the best choice for psychostimulant tolerance due to another property that it has. I will talk about that towards the end though.





3) I have a bit of confusions with studies with NMDA antagonists and amphetamine/stimulants. Why do these studies say that a "reverse tolerance" occurs after repeated administration and an NMDA antagonist blocks this? These seem contradictory to what I thought usually happened when one repeatedly takes stimulant medications and drugs. Perhaps someone can help me.



Medieval has a big thread posted over at bluelight.ru with a collection of studies showing NMDA antagonist effectiveness to treat tolerance for a variety of drugs including opioids, ethanol, amphetamines, stimulants such as cocaine and amphetamine, and then their effect on general dopamine and serotonin systems. Not sure if I'm supposed to post links to other forums, but here is the link: http://www.bluelight.ru/vb/showthread.php?t=501875 (mods just remove this if I'm in the wrong).



Pretty much all of the studies in that first post there show the effectiveness of NMDA antagonists towards reducing tolerance (either general or a few different varieties of measures of the drugs effects such as stereotypy, locomotor activation, etc.) to those substances, except for the ones cited for stimulants. In fact, they are quite strange. Medievel does make a note here saying "unfortunately i found references regarding sensitization, it is established however that NMDA antagonists upregulate several dopamine receptors and it is backed up by many members that used it successful for stimulant tolerance".

Life Sci. 1989;45(7):599-606.

Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801.



Karler R, Calder LD, Chaudhry IA, Turkanis SA.



Department of Pharmacology, University of Utah School of Medicine, Salt Lake City 84132.

Abstract



"Reverse tolerance" was produced in rats and mice by repeated exposure to either cocaine or amphetamine. The locomotorstimulant effect was studied in mice; stereotypy and convulsions in rats. MK-801, the NMDA antagonist, blocked the development of "reverse tolerance" to all three effects. In contrast, haloperidol selectively blocked "reverse tolerance" to cocaine-induced stereotypy but not to convulsions. The data suggest that the glutamate system participates in the mechanism of "reverse tolerance" to the dopaminergic effects of cocaine and amphetamine, as well as to the convulsant effect of cocaine.

So, a "reverse tolerance" or strengthening of effects of the drug occurred when the rats were repeated exposed to the stimulants. In fact, this happened to three of the main effects usually observed from these stimulants in mice: locomotorstimulant, stereotypy, and convulsions. Then, the NMDA antagonist blocked this reverse tolerance effect. I tried researching this reverse tolerance phenomenon but it just confused me more. Perhaps someone can explain. Why would this contradict the theories and anecdotal reports around the web in a variety of ways? Perhaps when one translates these effects observed upon the mice into human terms, they are not necessarily the specific beneficial effects that a human is looking to achieve from use of amphetamines or cocaine and that they actually represent the exacerbation of side effects of the drug as is it is continually used. Or, perhaps a sensitization to these effects in rats and a blockade of the sensitization of these effects with an NMDA antagonist translates into the opposite in human terms. I'm not sure. Help

Prog Neurobiol. 1998 Apr;54(6):679-720.

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants.



Wolf ME.



Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Il 60064-3095, USA. wolfm@mis.finchcms,edu

Abstract



Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans. Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A. (1989) Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801. Life Sci., 45, 599-606]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization. To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors. While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry, EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons. The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.

Once again mentions how repeated administration causes "sensitization" and how NMDA and AMPA metabotropic glutamate receptors participate in that.

Nihon Arukoru Yakubutsu Igakkai Zasshi. 2002 Feb;37(1):31-40.

[Alteration of neuronal activities following repeated administration of stimulants].



[Article in Japanese]



Amano T, Matsubayashi H, Sasa M.



Department of Pharmacology, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.

Abstract



It has been well-known that abuse of psychostimulants such as amphetamine and methamphetamine (MAP) induces behavioral sensitization (reverse tolerance) to MAP, resulting in psychotic effects such as hallucinatory-delusional state. Animals treated with MAP repeatedly also show the behavioral sensitization to MAP. This paper focuses on the pathogenesis and mechanism underlying sensitization to MAP after repeated treatment with MAP. MAP is known to release dopamine (DA), noradrenalin (NA) and serotonin (5-HT), and bind with the same sites on DA-, NA- and 5-HT-transporters as do these monoamines, thereby inhibiting re-uptake of these substances. As a result, these monoamines accumulate in the synaptic areas unnerved by the monoamine systems. An increase in the monoamines also occurs in the dendritic areas of DA, NA and 5-HT cells probably by a mechanism similar to those in the presynaptic terminals of monoamines. Releases and syntheses of DA, NA and 5-HT are inhibited by the monoamine per se via their autoreceptors such as D2, alpha 2 and 5-HT1A receptors, respectively. It is noteworthy that repeated MAP treatment results in the reduction of DA transporters, and such a decrease in transporters has been also found in MAP abusers by PET studies, suggesting a decrease in DA transporters is related with the appearance of reverse tolerance. Repeated MAP administration induces immediate early gene such as c-fos, c-jun and arc, and the increase in arc is inhibited by D1 and NMDA antagonists, suggesting an important role of such genes in inducing reverse tolerance. In electrophysiological studies using anesthetized rats treated with MAP repeatedly, hyposensitivities and hypersensitivities to DA and MAP have been found in nucleus accumbens receiving dopaminergic input from ventral tegmental area, 24-30 h and 5 days after the final administration of MAP, respectively, although the sensitivities recovered to the normal level 10 days after the treatment. The hypersensitivities were probably mediated via D1/D2 receptors. Thus, the hypersensitivities of nucleus accumbens neurons to DA and MAP are actually completed after repeated treatment of MAP. Therefore, it is of great interest to elucidate the molecular mechanism responsible for the DA receptor hypersensitivity.

Once again this mentions the "reverse tolerance" effect produced after repeated administration. It says a little about NMDA antagonists; although it does mention how an "increase in arc" is inhibited by D1 and NMDA antagonists; it also highlights how a decrease in DA transporters could be related to "reverse tolerance" as well.



So, obviously I'm confused about this whole sensitization with repeated administration of stimulants in mice. I'm guessing it can be translating into humans as "tolerance" somehow. Someone explain?



Then, there's a bunch of citations mentioning how NMDA receptors can help to upregulate DA (mostly this) and serotonin receptors in that post of Medievil's. As said in that last study there, DA transporters are related to "reverse tolerance". A few other abstracts along with a large consensus of the medical community and brotelligence seem to agree with this:



Chronic amphetamine: is dopamine a link in or a mediator of the development of tolerance and reverse tolerance? Kuczenski R, Leith NJ. Pharmacol Biochem Behav. 1981 Sep;15(3):405-13.

"Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism."



http://www.ncbi.nlm.nih.gov/pubmed/17608145

Dopamine receptor antagonists reverse amphetamine-induced behavioral alteration on a differential reinforcement for low-rate (DRL) operant task in the rat.

Cheng RK, Liao RM. Department of Psychology, Research Center for Mind, Brain, and Learning, National Cheng-Chi University Taipei 116, Taiwan, Chin J Physiol. 2007 Jun 30;50(3):149. Chin J Physiol. 2007 Apr 30;50(2):77-88.

"Together, these results suggest that the dopamine D1 and D2 receptors are involved and important to the temporal regulation of DRL response under psychostimulant drug treatment. Furthermore, this highlights the involvement of the brain dopamine systems in the temporal regulation of DRL behavior performance."



So, the Dopamine system is involved in the effects of stimulants and is one of the ways tolerance is modulated.

[Taal]

..... and NMDA antagonists tend to upregulate these receptors.

Medivals thread cites this:

(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.

5) In looking at those studies I posted in that first post up there. They tend to allude me to ask this:

Can Memantine's neuroprotective effect when administered with MDMA or METH actually be attributed to a blunting of the desired effects one would take those drugs for anyway? A few statements up there lead me to believe this:

Results of the probe trial demonstrated that MDMA-treated rats did not remember the location of the platform, but this memory impairment was also prevented by the MEM pre-treatment. Moreover, MEM alone improved the learning task.

Well, noone wants memory loss on MDMA so thats good.

MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes.

Working as a antioxidant...this is good. Reactive oxygen species probably don't contribute to desired user effects.

This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987).

Hmmmm....perhaps MEM wasn't working as an antioxidant, it was just preventing the reactive oxygen species from ever being formed due to its alpha-7 nAChR antagonistic properties. Still...thats not necessarily bad for desired user effects.

In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM

Hmmmm....isn't MDMAs desired user effects thought to occur because of the decreased 5-HT uptake? That would mean it would blunt those effects.

A similar pattern (in regards to how MEM inhibited the decrease of 5-HT by MDMA) was observed when we measured the dopamine transport inhibited by METH.

Hmmmm....isnt amphetamine's desired user effects thought to partially occur because of an inhibition of dopamine reuptake?

We conclude that MEM prevents MDMA and METH effects in rodents.

That's a bit more straight statement from the authors. Although the word "effects" is quite vague. Which effects..there are many. Would need the full text to look deeper.

MDMA (50 microM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 microM). This effect of MEM was fully prevented by PNU 282987 (0.5 microM).

Once again, looks like an antioxdiant.....nope its just preventing the production of the ROS probably because of alpha-7 nACHR antagonism.

A single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment.

Well the hyperthermia effect of MDMA wasn't prevented my MEM, that would be awesome if it did.

It can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR.

But what if alpha-7 nAChR was one of the avenues that MDMA exerted its desired user effects? Fail.



So, correlating with alot of peoples advice, my personal account, and (some, but not all) anecdotal accounts Memantine actually may work as a neurprotectant simply by preventing MDMA or amphetamines (METH at least in these studies) from working properly and giving the user their desired effects.



Would like input here.



Alluding to that last statement up there have to do with alpha-7 nAChR (under study #3):

MDMA and METH may have some similar pharmalogical mechanisms of exerting their effects since they are are kind of close relatives.

The results of those three studies examining the neuroprotective effects of Memantine do tend to show that this may be true in that they both somehow work through alpha-7 nAChR.



This leads me to what I was alluding to before in this unnecessarily long post.



The theories on the net seemed to point towards using NMDA receptor antagonists to reduce tolerance to the desired user effects of amphetamines by perhaps regulating the flow of glutamate and/or upregulating the NMDA receptors. Memantine was used for this purpose because it was an NMDA antagonist

that tended to have a low side effect profile, good safety, neuroprotective effects, antidepressant effects, and the added benefit of improving cognition in some individuals by, in theory, upregulating alpha-7 nAChR after the brain fog subided. Also, brotelligence echoed stories of its glory.

[Taal]

On my pubmed marathon last night I came across these that you may or may not have seen before (I don't think I've seen anyone reference this):

Eur J Neurosci. 2004 May;19(10):2859-70.

Long-lasting nicotinic modulation of GABAergic synaptic transmission in the rat nucleus accumbens associated with behavioural sensitization to amphetamine.



de Rover M, Mansvelder HD, Lodder JC, Wardeh G, Schoffelmeer AN, Brussaard AB.



Department of Experimental Neurophysiology, Institute for Neurosciences (INW), Centre for Neurogenomics and Cognitive Research, Vrije Universiteit, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.



A robust increase in dopaminergic transmission in the nucleus accumbens (NAc) shell has been reported to be consistently associated with the long-term expression of behavioural sensitization to drugs of abuse. However, little is known about how this affects the neuronal network of the NAc. We made cellular recordings in NAc slices of saline- and amphetamine-pretreated adult rats and found that expression of behavioural sensitization was associated with long-lasting changes in the basal firing pattern of cholinergic interneurons up to 3 weeks after the last drug injection. Consequently, upon amphetamine sensitization, an inhibiting effect of the nicotinic receptor blocker mecamylamine on the amplitudes of spontaneous GABAergic synaptic currents as well as on the failure rate of electrically evoked GABAergic currents was found that was not present under control conditions. Thus, behavioural sensitization to amphetamine is associated with an up-regulation of the endogenous activation of nicotinic receptors that, in turn, stimulate the GABAergic synaptic transmission within the NAc shell. This is a new mechanism by which drugs of abuse may induce alterations in the processing and integration of NAc inputs involved in psychomotor sensitization.

J Neurosci. 2002 Apr 15;22(8):3269-76.

Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation.



Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ.



Drug Abuse Program, Research Institute Neurosciences Vrije Universiteit, Department of Medical Pharmacology, Vrije Universiteit Medical Center, 1081 BT Amsterdam, The Netherlands. anm.schoffelmeer.pharm@med.vu.nl



Animal studies have shown that nicotine and psychostimulant drugs (amphetamine and cocaine) share the property of inducing long-lasting behavioral and neurochemical sensitization, which is thought to contribute to their addictive properties. Neuroplasticity subserving learning and memory mechanisms is considered to be involved in psychostimulant-induced sensitization and addiction behavior. Because nicotinic receptors in the brain play a role in the storage of drug-related information underlying reinforcement learning, we evaluated the possibility that activation of central nicotinic receptors may underlie psychostimulant-induced sensitization. Repeated exposure of rats to nicotine profoundly enhanced the psychomotor effects of nicotine and amphetamine 3 weeks after nicotine pretreatment. Moreover, the nicotinic receptor antagonist mecamylamine completely blocked the induction, but not the long-term expression, of behavioral sensitization to amphetamine in amphetamine-pretreated rats. Mecamylamine also prevented the development of cocaine-induced behavioral sensitization. Behavioral sensitization induced by nicotine, amphetamine, or cocaine was associated with an increase in the electrically evoked release of [(3)H]dopamine from nucleus accumbens slices. Coadministration of mecamylamine during pretreatment with nicotine, amphetamine, or cocaine prevented the development of this long-term hyperreactivity of nucleus accumbens dopamine neurons. Similarly, the high-affinity non-alpha7 subtype nicotinic receptor antagonist dihydro-beta-erythroidine prevented the development of amphetamine-induced behavioral and neurochemical sensitization. These data indicate that nicotinic receptor activation (by endogenously released acetylcholine) is a common denominator initiating neuroplasticity involved in the development of amphetamine, as well as cocaine-induced sensitization.

So, an additional mechanism by which tolerance to psychostimulants is modulated has to do with the nicotinic receptors. Now, these studies do say some confusing things to me too that hopefully someone can clear up, such as the first one that says "behavioural sensitization to amphetamine is associated with an up-regulation of the endogenous activation of nicotinic receptors".



Well, if we look at those other studies previously cited by Medieval about NMDA antagonism, they seem to indicate that "behavioral sensitization" or "reverse tolerance" can be prevented with an NMDA antagonist. Practically or anecdotally (at least at first glance), this seems contradictory - or maybe I just am interpreting it wrong, lol. So, in some way these phrases may translate to the "development of tolerance to the desired user effects" of these drugs.



If that is the case, then study #2 reveals that a nicotinic receptor antagonist would help to prevent tolerance to some of the effects of psychostimulants. I believe that study #1 is also saying that but, to me, it seems to be saying the opposite (tolerance (they say "behavioral sensitization" would occur due to an up-regulation of activity?). Perhaps I am interpreting it wrong.





So, now, despite some of its side effects on sleep that I mentioned a long time ago, Memantine seems to be the perfect agent for reducing or perhaps preventing during co-administration (although this may blunt desired user effects) psychostimulant tolerance since it has both antagonism on the alpha-7 nicotinic receptors and NMDA receptors - both of which may be involved in the pharmacological mechanism by which psychostimulants exert some of their effects. This is assuming that the alpha-7 nicotinic receptors and the selective nature of Memantine's NMDA antagonism work on the same receptors that these psychostimulants interact with. This is also assuming that Memantine actually has an upregulating effect on these receptor systems.



However, two problems with this is that I still do not understand why one would ever take Memantine at the same time they took a psychostimulant, even after working up in dosage for a week or more and letting the "brain fog" clear as it would most likely blunt many (but perhaps not all) of the desired user effects. In addition to this, it seems that Memantine's half life is so long (40-60 hours) that one would have to wait a full 2-3 days or more before it is completely out of their system and would not antagonize the desired user effects of said psychoactive substances.



Thoughts?





6) Alright, last thing, I swear.



NAC is a really good idea to take with psychostimulants because it may provide two TOTALLY AWESOME benefits (Directly relevant study referenced below.):



1) Prevent neurotoxicity and associated damage by working as a very potent antioxidant when administered with amphetamines.

2) Preventing a reduction in dopamine transporter (DAT) cause by amphetamines in the stratium and perhaps in other areas amphetamines interact. This is awesome because various downregulations and changes in the DA system is thought to be one of the causes (in addition to potentially the nicotinic and NMDA systems) for tolerance to some effects of amphetamines as referenced by some of those studies way up there.

http://www.ncbi.nlm.nih.gov/pubmed?term=15199373

Protective Effects of N-acetyl-L-cysteine on the Reduction of Dopamine Transporters in the Striatum of Monkeys Treated with Methamphetamine.



Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M.



Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.



Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant

drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [(11)C]beta-CFT. In contrast, the binding of [(11)C]SCH 23390 to dopamine D(1) receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans. Neuropsychopharmacology advance online publication, 16 June 2004; doi:10.1038/sj.npp.1300512.

Hopefully and probably more than likely not, NAC doesn't block the desired user effects of psychostimulants with its neuroprotective mechanism of action. I'd say it has a lesser chance to than something that antagonizes one of the systems that they could directly work through (nicotinic or NMDA). Perhaps the full text would reveal the answer. Take your NAC with your Adderall, kids.



Alright I need to go do something more productive now.

[kassem23]

It seems you may have overlooked this thread.



I'll quote it below.

It is well established that psychostimulants, including amphetamine, have been shown to increase extracellular glutamate in the nucleus accumbens (NA) to levels of hyperexcitation ([1], [2], [3], [4]).



As a result of this glutamate hyperexcitation, NA core (NAc) dopamine (DA) sensitivity is downregulated. It has been found in [5], in rats chronically treated with amphetamine, NA DA neurons were significantly less sensitive to glutamate excitation.



NAc DA sensitivity has large implications for motivation, though. [6] provides a thorough review of just this idea. It mentions studies that have proven 'NA DA depletions... impair activational aspects of motivation.' Certainly, it is plausible that these feelings of motivation can have a positive, therapeutic effect on ADD treatment.



Additionally, [5] also found that chronic amphetamine exposure has been shown to increase and decrease, respectively, the responsiveness of NAc neurons to glutamate. This closely matches anecdotal reports of subjective increases in mood and motivation during the beginning of stimulant therapy which then taper off as effects of stimulant treatment normalize.



One possible solution to controlling this glutamate hyperexcitation to restore sensitization of NAc DA neurons and the therapeutic motivational effects of amphetamine is coadministration with memantine. Memantine is an uncompetitive antagonist at glutamatergic NMDA receptors. Most importantly to our purposes, because memantine has a low-to-moderate affinity for NMDA receptors, it does not seem to block normal glutamate transmission; rather, it reduces abnormal neurotransmitter-mediated activation of the receptors [7], thereby potentially reducing excitotoxic neuronal damage. Normal glutamate function, then, is not impinged upon.



Memantine is very well tolerated ([8], [9], [10]) and does not have drug-drug interactions with amphetamine [8]. Also, memantine has been studied in healthy, non-dementia patients with no signs of problems and, in fact, showed evidence of cognitive enhancements and other beneficial effects in these patients ([11], [12], [13]). It also provides beneficial, healthful side effects, including an increase in BDNF [14].



Theoretically, co-administration of memantine and amphetamine is a safe, novel, and promising solution to restore NAc DA sensitivity that is lost by amphetamine-induced glutamate hyperexcitation and, as a result, restore the plausibly therapeutic motivational effects of amphetamine lost in the early stages of treatment.

That is, at least, the consensus on how Memantine can be effective adjunct to amphetamine treatment. Sorry for not elaborating, but I do not have much time.

Have you or anyone else experienced effects like these? I read alot of reports saying that they would end up sleeping for a very long time or being drowsy a large part of the day.

If you read my thread, here, you'll see I have some trouble with Memantine and sleep, now as well.



I just ran out, so didn't take my 10 mg Memantine dosage before sleep, but before, and every-time I've taken 10 mg before sleep, I can sleep +12 hours without waking and I need one hell of an alarm clock to get up in the morning. Plus, the sleep doesn't seem very restful at all. Also, if I am woken after say 7 hours of sleep, I have a horrible time getting up. I can literally not shake the tiredness of me. After a cup of coffee and my 5 or 10 mg dosage of d-amphetamine, however, I am really refreshed.



Also, check this post on a letter response to the original study (http://www.ncbi.nlm.nih.gov/pubmed/15522999) suggesting that Memantine's efficacy may be limited, because only its NMDA antagonism is beneficial, and its alpha-7 antagonism will counteract its positive effects (that is the study's reasoning).

[Taal]

It seems you may have overlooked this thread.

Actually I think I have read that thread about 5 or more times and probably your post many more times than that. It is one of my favorites on this topic. I think that your summarization of research in regards to this is great. However, I have a few questions/comments about it. My comments are in bold.

It is well established that psychostimulants, including amphetamine, have been shown to increase extracellular glutamate in the nucleus accumbens (NA) to levels of hyperexcitation ([1], [2], [3], [4]).



As a result of this glutamate hyperexcitation, NA core (NAc) dopamine (DA) sensitivity is downregulated. It has been found in [5], in rats chronically treated with amphetamine, NA DA neurons were significantly less sensitive to glutamate excitation.



NAc DA sensitivity has large implications for motivation, though. [6] provides a thorough review of just this idea. It mentions studies that have proven 'NA DA depletions... impair activational aspects of motivation.' Certainly, it is plausible that these feelings of motivation can have a positive, therapeutic effect on ADD treatment.



Additionally, [5] also found that chronic amphetamine exposure has been shown to increase and decrease, respectively, the responsiveness of NAc neurons to glutamate. This closely matches anecdotal reports of subjective increases in mood and motivation during the beginning of stimulant therapy which then taper off as effects of stimulant treatment normalize.



One possible solution to controlling this glutamate hyperexcitation to restore sensitization of NAc DA neurons and the therapeutic motivational effects of amphetamine is coadministration with memantine. Memantine is an uncompetitive antagonist at glutamatergic NMDA receptors. Most importantly to our purposes, because memantine has a low-to-moderate affinity for NMDA receptors, it does not seem to block normal glutamate transmission; rather, it reduces abnormal neurotransmitter-mediated activation of the receptors [7], thereby potentially reducing excitotoxic neuronal damage. Normal glutamate function, then, is not impinged upon.



This sounds great but here is one of the problems I see with it. First off, you use the word "coadministration" which could perhaps be interpreted vaguely. Do you mean "take at the same time as amphetamines", "take a few hours after taking the first dose of amphetamines", "take when you crash from amphetamines", or perhaps "take on the days you don't take amphetamines"? This could have big implications for the efficiency of treatment - I know you have recommended the protocol to me in another post and in other posts on this forum of taking the memantine without amphetamines until the brain fog subsides (which is about a week or more sometimes) and then taking the amphetamine. However, in this summarization you have left that part out/vague with use of the word "coadministration." Additionally, I also find it vague as to what exactly to do after one takes that first dose of amphetamine after waiting for the brain fog to subside from Memantine. Do you continue to take it each day with the amphetamine or is there a different protocol? This next point would have big implications for that question.



You say that Memantine "reduces abnormal neurotransmitter-mediated activation of the receptors." I am assuming that amphetamines would cause "abnormal neurotransmitter-mediated activation of the receptors." However, I would assume (just by general logic and also if you read those studies in the first post I made way up there especially the 2nd one) that amphetamine actually produces its subjective affects through the action of "abnormal neurotransmitter-mediated activation of the receptors." Therefore, if Memantine were to regulate this then it would also regulate the subjective effects of the drug on the user: a.k.a it would probably blunt the subjective effects. It could be one or any number and variety of effects the drug has on the user.



Thus, in an oversimplified sense, if you were to take Memantine and amphetamines at the same time you would simply have two drugs counteracting each other and might not even get the "activational aspects of motivation" effects you're looking for in the first place. If amphetamine does indeed produce the subjective user effects (one of them or some number) at the molecular level in this fashion and Memantine antagonizes this, then of course neither excitotoxic neuronal damage nor desensitization would occur; but it would also be pointless to take the amphetamines in the first place.



Now, there could be more details here or situations that I am missing and correct me if I'm wrong: for example, what if those diagnosed with ADD have abnormally low glutamate function. Amphetamines would increase this until it got to be too much and then Memantine put a cap on it: therapeutic effects are obtained without receptor damage or desensitization.



Additionally, perhaps the NMDA antagonism/gluatamate transmission regulation would sensitize this system to amphetamine's pharmacological mechanism through upregulation or something else...I'll talk about that in a bit.



Memantine is very well tolerated ([8], [9], [10]) and does not have drug-drug interactions with amphetamine [8]. Also, memantine has been studied in healthy, non-dementia patients with no signs of problems and, in fact, showed evidence of cognitive enhancements and other beneficial effects in these patients ([11], [12], [13]). It also provides beneficial, healthful side effects, including an increase in BDNF [14].



Although this is subjective (and somewhat nit-picky on my part), Memantine is very well tolerated if you compare it to some other options for NMDA antagonism such as Ketamine, DXM, PCP, etc. But, that IS definitely on a person by person basis. The experiences I have read of people having with it do vary quite a lot. For instance, some note that the brain fog never really went away even after the suggested time frame of a week - and even then experiencing crazy brain fog (even if it eventually goes away) isn't my favorite side effect.



Also, it definitely does do something to sleep as reference by mine, yours, others, and those references I provided. Whether or not its effect is beneficial or detrimental seems to do with individual experience (although that one study did note how rem and non-rem sleep cycles were abnormal). This is important because proper sleep is quite important for the effectiveness of amphetamines; although I don't have a citation handy this just is one of those common sense things.



There could be better alternatives for NMDA antagonism out there such as Acamprosate and perhaps especially Huperzine A (look at those studies I posted way above). Then again...these arn't as anecdotally tested on the internet for this purpose.



Theoretically, co-administration of memantine and amphetamine is a safe, novel, and promising solution to restore NAc DA sensitivity that is lost by amphetamine-induced glutamate hyperexcitation and, as a result, restore the plausibly therapeutic motivational effects of amphetamine lost in the early stages of treatment (Right here I'm really wishing that the phrase "without blocking subjective therapeutic effects" was added and then there was a solid citation after it so everyone's amphetamine tolerance issues could be easily and simply solved - but alas this is not here... ...).



I will say that in this last paragraph you hint at the idea of perhaps not doing a "by the book" co-administration and taking it on the off days with the hope that it would increase the rate at which tolerance to the desired therapeutic effects faded away.

Now, I am presuming (as I have stated before) that the current theory is to take the Memantine or said NMDA antagonist on amphetamine off days in the hopes that it will more quickly sensitize that system to one of the pharmacological mechanisms by which amphetamines produce their desired effects.



There are a three more main points I want to make in regards to your writing:



1) Is it actually proven to upregulate this system?:

Although I feel and probably sound quite lazy when I say this (I could probably prove myself wrong here when I say this), is it really proven that Memantine will actually upregulate/sensitize-to-amphetamines/restore the glutamate function/NMDA receptors? Does it do this through permanent structural changes or only temporarily while the drug is in the system? Does anyone have a citation for this? In theory it would be true, but has it been shown to?



2) Practical application of this method with the Memantine's half life:

Let's say that Memantine is able to upregulate the glutamate NMDA receptor system and decrese their tolerance to desired effects. Let's also say that Memantine blunts these beneficial effects through its NMDA receptor antagonism. You wouldn't want both to be in your system at the same time: that could be counterproductive. This would become especially difficult to manage since Memantine's half life is listed as 60-100 hours on (at least on Wikipedia it says that). Perhaps it excretes faster than that, perhaps the NMDA receptor antagonism isn't active the entire time, or perhaps there are ways to eliminate it faster (one erowid report suggested drinking a ton of cranberry juice).



3) Other mechanisms at work that could be effecting tolerance/adaptations to amphetamine's subjective effects:



What about treatment for these in addition to other avenues of doing so? These should be looked at too!



Although all of these systems are generally interconnected, there are other parts of it that could be focused on and treated as well. I talk about this in my mega-post. The predominate systems seem to be, at least to my understanding: DA neurons/system, the NMDA neurons/system, AND the nicotinic acetylcholine neurons/system. I have not really seen the nAChR really mentioned yet in regards to this topic. I talk about this last one at the end of my last post with citations. Here they are again anyway:



Eur J Neurosci. 2004 May;19(10):2859-70. "Long-lasting nicotinic modulation of GABAergic synaptic transmission in the rat nucleus accumbens associated with behavioural sensitization to amphetamine." de Rover M, Mansvelder HD, Lodder JC, Wardeh G, Schoffelmeer AN, Brussaard AB.

J Neurosci. 2002 Apr 15;22(8):3269-76. Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ. "Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation."



You seem to focus predominately on the NMDA neurons/system, which, admittedly, as you say effects the DA neurons/system too (hell, they are all interconnected).



But what about other avenues and thus treatments that could supplement this (such as nADhR antagonism)? What about ones that may not block the beneficial effects of amphetamines when administered at the same time (such as NAC - discussed above and below)?



The nADhR system and how it seems to have strangely been overlooked:



Luckily, and quite ironically (or is it?) Memantine has alpha-7 nADhR upregulating properties due, in theory, to it's alpha-7 nADhR antagonism. I will admit here that the specific type of nADhR antagonism that Memantine has, "alpha-7", may not be the correct form to actually sensitize the nADhR system to the pharmacological mechanisms of amphetamine in producing its desired effects; perhaps this is an overgeneralized theory. Who knows.



Regardless, this thought is very peculiar to me (in fact, this makes me think I may be missing something and completely wrong about this part):



The general consensus in addition to your advice seems to be to wait until the "brain fog" from Memantine is alleviated. Although there is slight ambiguity around here, this is more than likely or mostly (if it were to be a combatination of the NMDA and alpha-7 nAChR antagonism) due to Memantine's alpha-7 nADhR antagonism

(Aracava Y, Pereira EF, Maelicke A, Albuquerque EX (March 2005). "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 312 (3): 1195–205. doi:10.1124/jpet.104.077172. PMID 15522999.).



In a beneficially ironic way, waiting til the "brain fog" dissipates would signal upregulation of the nADhR system and thus perhaps tolerance reduction to the subjective effects produced by amphetamine's pharmacological action with these receptors.



However, I do not remember (correct me if I'm wrong or missing something) anyone mentioning this anywhere. You do not seem to mention it in your summarization anywhere. It just seemed to remain overlooked. Also, it may be too big of a generalization/assumption to believe that the specific alpha-7 nADhR antagonism will sensitize the entire system to amphetamine's pharmacological mechanism of action.



Thus, perhaps Memantine's primary tolerance reduction properties to the subjective effects (or certain specific effects) of amphetamines could be attributed to it's alpha-7 nAChRs antagonism in contrast to its NMDA receptor antagonism and glutamate regulation abilities.



This would agree with what you say here, too.



Additionally, I have made more comments in bold.

Also, check this post on a letter response to the original study (http://www.ncbi.nlm....pubmed/15522999) suggesting that Memantine's efficacy may be limited, because only its NMDA antagonism is beneficial, and its alpha-7 antagonism will counteract its positive effects (that is the study's reasoning). I'm not exactly sure what you mean when you say "efficacy".



Do you mean efficacy for tolerance to desired effects of amphetamines, towards potentially increasing cognitive performance in healthy adults like us by theoretically upregulating alpha-7 nADhR through antagonism to super-basline levels (or perhaps to back to baseline levels if it was somehow desensitized to below-baseline levels), or towards it's effectiveness against Alzheimer's correlating with the study?



The "efficacy" they seem to be talking about is in regards to Alzheimer's. Which does suck, but that mostly effects people with Alzheimer's. Although, this could be an indicator of an effect in healthy adults too.



You also say "its alpha-7 antagonism will counteract its positive effects". Which positive effects? If one were to apply it towards amphetamine tolerance reduction, hold the theory that the sensitivity of the nAChR system is a factor modulating amphetamine's tolerance to desired effects to be true, and if Memantine does indeed upregulate those receptors, then the alpha-7 antagonism would be a positive in and of itself (towards amphetamine tolerance reduction at least).



True, however, that it may cause too much brainfog in some people that never goes away. Perhaps there is a limit to the amount of alpha-7 fixing/sensitization that can occur - assuming it modulates the "brain fog" - maybe it can't go past baseline homeostatic levels.



Their conclusion here:

It is suggested that blockade of alpha7(*) nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well.

Not sure what exactly they mean by "early stages". Early stages of Alzheimer's or early stages of Memantine treatment?

Then again, having both properties (NMDA receptor antagonism and alpha-7 nADhR antagonism) probably doesn't hurt; although it probably increases the likelihood that it would block or blunt (or maybe even change in some way) the subjective beneficial affects when administered simultaneously with amphetamine.



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And now for a supplemental, healthy, non-blunting-to-desirable-effects, easy, practical, accessible, completely legal, and very-tolerable way to attenuate that tolerance you get to the -oh so sweet- desirable effects of amphetamine in addition to preventing damage to your dopamine system!:



NAC.



NAC may also attenuate tolerance to the beneficial effects of amphetamine.



I referenced one study in my previous post I was very excited about that I wanted to mention again:



"Protective Effects of N-acetyl-L-cysteine on the Reduction of Dopamine Transporters in the Striatum of Monkeys Treated with Methamphetamine."

Neuropsychopharmacology. 2004 Nov;29(11):2018-23.

Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M.



This study discusses the results of treating monkeys with the antioxidant NAC while they were administered METH which "significantly attenuated the reduction of DAT". Theoretically, attenuating the reduction of DAT could help keep the beneficial effects of amphetamines going too!



Hopefully, NAC's mechanism of action here does not also prevent amphetamine's mechanism of action in producing the desired effects when administered simultaneously like an NMDA or nADhR receptor antagonist theoretically could. More then likely it is due to it's ROS scavaging properties.



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Melatonin is also super badass.



Edit: Another addition (must..get..away..from..computer): I was trying to get away from my computer but then stumbled upon Melatonin's beneficial effects in regards to it's attenuation of neurotoxicity when administered with amphetamine; some other cool ones are stuff such as attenuating negative effects amphetamine has on mTOR and preventing tyrosine hydroxylase levels from decreasing. There a bunch more, too. BUT, I need to stop. My research addiction is starting to take over my life. Agh.



Hopefully melatonin doesn't blunt desired user effects too...that would suck. I need to get up before I try to research that too.



Citations!:



Melatonin attenuates the amphetamine-induced decrease in vesicular monoamine transporter-2 expression in postnatal rat striatum.

Neurosci Lett. 2011 Jan 20;488(2):154-7. Epub 2010 Nov 13. Mukda S, Vimolratana O, Govitrapong P.



Melatonin attenuates methamphetamine-induced overexpression of pro-inflammatory cytokines in microglial cell lines.

J Pineal Res. 2010 May;48(4):347-52. Epub 2010 Mar 31. Tocharus J, Khonthun C, Chongthammakun S, Govitrapong P.



Melatonin attenuates methamphetamine-induced reduction of tyrosine hydroxylase, synaptophysin and growth-associated protein-43 levels in the neonatal rat brain.

Neurochem Int. 2009 Nov;55(6):397-405. Epub 2009 May 4. Kaewsuk S, Sae-ung K, Phansuwan-Pujito P, Govitrapong P.c.



Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells.

J Pineal Res. 2009 Mar;46(2):199-206. Epub 2008 Nov 19. Kongsuphol P, Mukda S, Nopparat C, Villarroel A, Govitrapong P.



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Few other cool tidbits and ideas for amphetamine tolerance (no matter how unsafe they may be )



Propanolol inhibits amphetamine tolerance and metabolism.

(Don W. Shoeman, et al. "INHIBITION OF AMPHETAMINE TOLERANCE AND METABOLISM BY PROPRANOLOL." http://jpet.aspetjournals.org/content/191/1/68.short)





Metyrapone markedly potentiates d-amphetamine perhaps by inhibiting the enzyme that metabolizes it.

(Marrow L, Statham A, Overton PG, Brain PF, Clark D. Addict Biol. 1999 Jan;4(1):89-92. "The corticosteroid synthesis inhibitor metyrapone markedly enhances the behavioural effects of d-amphetamine." http://www.ncbi.nlm.nih.gov/pubmed/20575775)

(Reid MS, Ho LB, Tolliver BK, Wolkowitz OM, Berger SP. Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment. Brain Res. 1998 Feb 2;783(1):133-42.)





Pyridine (NVP), which seems to be a random experimental substance, increases amphetamine levels and may inhibit metabolism of it.

(Salama AI, Goldberg ME. Elevation of amphetamine levels in rat brain after administration of the choline acetyltransferase inhibitor 4-(1-Naphthylvinyl) pyridine (NVP). Arch Int Pharmacodyn Ther. 1975 Jun;215(2):197-201.)





Lol don't take Ibogaine with amphetamines:

("These and other data suggest that ibogaine irreversibly inhibits an amphetamine-metabolizing enzyme."

Glick SD, Gallagher CA, Hough LB, Rossman KL, Maisonneuve IM. Differential effects of ibogaine pretreatment on brain levels of morphine and (+)-amphetamine. Brain Res. 1992 Aug 14;588(1):173-6.)





Alright, I need to stop myself from writing and posting citations.



I'm going to actually take a shower now and go buy some NAC, (edit: melatonin too), Huperzine A, and L-trypophan (Leccese AP, Lyness WH. Brain Res. 1984 Jun 11;303(1):153-62. "The effects of putative 5-hydroxytryptamine receptor active agents on D-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesions." http://www.ncbi.nlm.nih.gov/pubmed/6610461).

[Ex Dubio]

As to the original post, indeed memantine does seem to be one of the most viable solutions for reducing amphetamine toxicity. Of course, given that it's still not entirely known to what extent amphetamine is toxic at therapeutic dosing, this may or may not be relevant with therapeutic use. However, it's an interesting idea for sure if one plans to use amphetamines recreationally.



Note that kassem is also on the mark in that acute memantine seems to attenuate amphetamine's effects, whereas chronic memantine inhibits tolerance.

1) I found that Memantine has this very strange effect on sleep for me. Usually, when going natural, I sleep for quite a while 8-10 hours, but tend to have moderate trouble getting up in the morning. If I drink heavily before going to sleep, then I only sleep for about 5 hours then wake up and can't get back to sleep. I will feel slightly sleep deprived and "out of it" then. I have heard/read that alcohol can disrupt sleep architecture. Additionally, a similar phenonmenon happens when taking stimulants that are affecting me when I go to sleep like caffeine or amphetamine. It especially happened when I used to take AMP (that old energy product). I'd wake up not really feeling like I need more sleep and not being able to get back to sleep; but, I would still feel a bit "out of it" like I'm lacking something in my brain. It's hard to put into words. It does make sense, though...stimulants would also disrupt sleep architecture.



Now, with Memantine a similar phenomenon is happening to me. I will sleep (usually for exactly 7.5 - 8 hours) and then just wake up not being able to get back to sleep. I feel better than I do when I attempt to sleep with alcohol or stimulants, but something is still "off". I feel like I didn't get something that I needed during sleep. The feeling is definitely separate from the brain fog; although, it may be contributing in a very small way.

All of these effects are consistent with poor sleep quality, IMO. Are you noting these effects with chronic or acute memantine? Also note that NDMA antagonists have some effects associated with increasing PFC NE and generally enhancing wakefulness. This would contribute to poor sleep quality and might explain the resemblance to stimulant-induced poor sleep quality. Note that you can find a reference in (PMID: 19007758).

Sometimes I take diphenhydramine or doxylamine succinate. These have always made me sleep for about 10-12 hours and wake up at something like 2 or 3 o'clock when only taking 25mg of one of those (never combined them). It would be extremely difficult to get up, and I'd feel quite groggy. Now, even if I take 50mg of diphenhydramine and 50mg doxylamine, I wake up 8 hours later and feel exactly the same as if I hadn't taken either. Normally, having that sort of dose would put me out for a WHILE and I'd feel preeettty horrible.

I gather this is with chronic memantine? This is consistent with chronically increased cholinergic neurotransmission. A number of the effects of antihistamines are actually due to their ability to block muscarinic receptors. Increase generalized cholinergic transmission, and the side effects are attenuated. You see similar results using CDP-choline or huperzine. Note that memantine has been noted to increase general cholinergic transmission, particularly in the hippocampus (PMID: 18198419).



Furthermore, the above-referenced (PMID: 19007758) notes that orexin and an NMDA antagonist each increase wakefulness and cortical NE, but in combination they nullify each others' effects. If the antihistamines' antihistaminergic effects are responsible for the "hangover", then the perceived effects may result in part from a reduction in orexin-mediated PFC NE release. (I don't recall the details of histamine/orexin interaction, but IIRC they are tightly intertwined.) An NMDA antagonist would correct, at least in part, for the deficit in PFC NE release.

Also, since taking it, amphetamine withdrawal was completely abolished. Normally, if I took amph with a high frequency and moderately high quantity , about 2 days after the last dose I would feel extremely lazy, flat mooded, and not motivated to do anything at all.

This simply goes along with an attenuation of mesolimbic NMDA activation. Chronic mesolimbic NMDA activation results in relatively long-term changes that reduce basal DA outflow. Memantine blocks this effects and thereby not only reduces tolerance, but also withdrawal. Keep in mind that tolerance is in some sense a homeostatic response to taking a given drug; withdrawal is the process of reversing that homeostatic response.

I theorize that these would mostly be attributable to Memantine's D2 agonism, but I'm not sure. Correct me if you believe otherwise. D2 agonism property is cited from Wikipedia which cites:

Seeman P, Caruso C, Lasaga M (February 2008). "Memantine agonist action at dopamine D2High receptors". Synapse 62 (2): 149–53. doi:10.1002/syn.20472. PMID 18000814.

Memantine is a D2 agonist, but it's quite weak. What effects are you attributing to D2 agonism? None of what you've discussed above is likely related to D2 agonism.

Reason I'm worried about this is because I have personally realized as well as read from others that getting the proper quantity, quality, type, and phases of sleep is a huge factor in how effect amphetamine is at its desired effects.

How much memantine are you taking, how long have you been taking it, and when are you taking it? Many of the effects can be attenuated by either time or a change in dose.

I also came across a few studies in regards to Memantine. It definitely does something to sleep.



Side note: Interestingly in this study, Memantine was found to be a D1 agonist and found not to be a D2 agonist. This contradicts that first study I cited up top from wikipedia that say it IS a D2 agonist. Strange. All the japanese people I know were smart in school, so they were probably correct on this one

Jk, I like russians too...

The first study is completely irrelevant to healthy humans.



The second study isn't suggesting that memantine disturbs sleep structure, but rather that it functions somewhat like a psychostimulant, which it does. The authors note that the wakefulness-enhancing effects were likely due to D1 stimulation, and they're likely right, but only indirect to NMDA antagonism. Sleep is controlled by structures within and surrounding the mesolimbic system (sleep, stress, and motivational salience are intertwined there, in some sense) and by enhancing mesolimbic DA release, memantine's NMDA antagonism results in psychostimulant-like effects, including wakefulness.



So the authors aren't actually implying memantine is a D1 agonist, as they say nothing about direct binding to the receptor. Instead, memantine increases mesolimbic DA concentrations and thereby results in [highly indirect] D1 agonism. (Note that the term "D1 agonist" is typically reserved for direct agonists.)

There's more studies on pubmed about this, but I'll spare you. Looks like Memantine messed with non-rapid and rapid eye movement sleep cycles in the Japanese study with rats, effected sleep cycles (I believe negatively, but not sure) in the Russian study in rats, and helped sleep in humans with Parkinson's and Lewy bodies disease in the Swedish study that were effected by "probably REM sleep behavior disorder".

The rat study, as mentioned before, is on a specific genetic line that likely has no relevance to healthy humans. The Russian study did not indicate a disruption of sleep, but rather psychostimulant-like properties. (In other words, memantine should not be taken -- acutely at least -- at bedtime.) The last study doesn't necessarily have relevance to sleep in healthy humans, as it did not alter REM sleep structure outside of reducing REM sleep behavior disorder, which is a specific pathology.

[Ex Dubio]

I'm curious as to why you all are exactly suggesting to not take amphetamines but instead take a week or more off while slowly increasing in dose and allowing brain fog to alleviate (theoretically waiting for the alpha-7 nicotinic receptors to upregulate). There are a few strange things around this:

Amphetamine use results in activation of mesolimbic NMDA receptors and this mechanism is, in large part, responsible for tolerance to many of the effects of amphetamine. By removing amphetamine, taking memantine, and then adding amphetamine in, you enable the mesolimbic system to at least partially return to baseline and then add amphetamine back while blocking NMDA receptors, thereby preventing future tolerance.



In other words, depending on the dose of memantine, memantine may be able only to prevent tolerance, not necessarily reverse it. This is why one might stop amphetamine before taking memantine, wait a week, and then return to taking amphetamine.



This is mostly related -- based on the reigning theory of NMDA's action in the mesolimbic system -- to NMDA, not alpha-7, modultaion.

-People around the net and various forums all seem to be doing something different, recommending something different, and reporting various results with this. For instance, some guy over at the addforums is reporting just starting out on 10mg a day and that that is having tremendous effects the alleviation of his tolerance to his specific desired effects of amphetamines. I realize effects from drugs do vary from person to person.

Don't take this the wrong way, but most health forums on the net are filled with so much misinformation they are nearly impossible to navigate. Yes, experiences vary from person to person, but often individuals also leave out key elements of their circumstances, making generalizations quite tricky. Regardless, I don't see how this contradicts the original idea.

-I believe the general consensus is the brain fog is contributed to the alpha 7 nicotinic receptor antagonism (assuming these are separate from the NMDA antagonism and I'm not corrected). At least, that's what alot of people seem to have posted. I know on wikipedia, it says that with a citation:



Wiki:



Citations:

1)Mol Pharmacol. 1998 Mar;53(3):555-63. "Open-channel blockers at the human alpha4beta2 neuronal nicotinic" acetylcholine receptor. Buisson B, Bertrand D. Department of Physiology, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland.

2)Buisson B, Bertrand D (1 March 1998). "Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor". Mol Pharmacol. 53 (3): 555–63. PMID 9495824. http://molpharm.aspetjournals.org/cg...g&pmid=9495824.

3)Aracava Y, Pereira EF, Maelicke A, Albuquerque EX (March 2005). "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 312 (3): 1195–205. doi:10.1124/jpet.104.077172. PMID 15522999.

But the idea of temporarily stopping amphetamine has nothing to do with brain fog and everything to do with memantine's ability to prevent, but not reverse, tolerance.

Upon further investigation, I could only find reasoning that the alpha 7 nAChR antagonism was responsible for the initial brain fog in citation #3 from wikipedia:

"It is suggested that blockade of alpha7 nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well."



Citations #1 and #2 just seemed to say it was an alpha7 nicotinic receptor antagonist. I believe they were referencing previous sentences in the article.

And it is fairly well accepted that the initial brain fog is due, at least in part, to alpha-7 nAChR antagonism. But this isn't the reason for temporarily stopping amphetamine, as I mentioned above.

I'm not sure about the NMDA antagonism interfering with cognition as there are other substances that have NMDA antagonist properties that do not seem to interfere with cognition such as Huperzine A (some citations about its NMDA antagonism later) or simply magnesium. However, perhaps Memantine's antagonism works in a different way or on different specific receptors within the NMDA subcategory such as "low baseline glutamergic signalling" like you said and this accounts for or has an additive effect to its initial cognitive decline; It is a "selective NMDA antagonist" according to wiki however accurate and relevant that may be.

This is going to depend heavily on the dose and NMDA affinity. High doses of ketamine, a potent NMDA antagonist, have disassociative anaesthetic properties and can stop higher thought in its tracks. Sufficient doses of NMDA antagonists certainly can interfere with cognition, but it is not out of the question that low doses might, particularly with chronic treatment, improve cognition. This is at least part of the explanation for memantine's positive effects on cognition with chronic treatment.



Note that huperzine A is a more potent AChE inhibitor than it is an NMDA antagonist. AChE inhibition has fairly potent pro-cognitive properties. At the kind of doses at which it's used, I imagine AChE inhibition would mask any cognitive effects of NMDA antagonism. Magnesium, on the other hand, is an NMDA antagonist, but is an extraordinarily weak one compared to the compounds we're discussing.



Another part of the equation is that memantine has unusual kinetics, as it manages to bind and unbind from the NMDA receptor very rapidly. The end result is that memantine acts as only a weak antagonist of NMDA where (and when) there are normal levels of glutamate in the synapse, but works as a comparatively stronger antagonist when levels of glutamate are higher. This allows it to maintain normal cognition while blocking excitotoxicity.

Lets say the brain fog has nothing to do with Memantine's NMDA antagonist properties for a bit (as you said yourself, you're not sure either):



If Memantine's non-competitive NMDA antagonist activity is what we're looking for, then isn't that generally completely separate from its alpha-7 nicotinic receptor antagonism or am I wrong here. I mean, sure, we're waiting for those receptors to upregulate so that we get the theoretical and anecdotally noted cognitive enhancement from it, but, theoretically, that shouldn't have much to do with amphetamine's receptor profile or effects. Right? So then why abstain from amphetamine use while starting Memantine?

It's not entirely clear, unless you've seen evidence otherwise, that memantine's pro-cognitive effects derive from alpha-7 antagonism [and consequent upregulation]. Memantine's effects on NMDA cannot be discounted as potentially enhancing cognition, particularly under specific sets of circumstances. But yes, NMDA antagonism is a distinct property from alpha-7 antagonism. There are plenty of drugs that have one property, but not the other.



Again, the reasons for abstaining for amphetamine related to memantine's lesser ability to reverse than to prevent amphetamine tolerance.

Side note: After doing a bit of searching last night on this I found some REALLY interesting studies that seem to highlight a property/mechanism of amphetamine that I do not believe has been mentioned at any forums before (or at least I hope not otherwise I'll look retarded) and has huge relevance to Memantine's ability to lower amphetamine tolerance. I'll talk about these soon.

Do tell. But NMDA antagonism is pretty well-accepted as the mechanism behind memantine's ability to attenuate amphetamine tolerance. Keep in mind that other NMDA antagonists unrelated to memantine -- like DXM -- also lower amphetamine tolerance.

Also, although Memantine is definately a good candidate for the NMDA antagonism job, I'm curious as to why it is the NMDA antagonist of choice? I know one of the reasons is because of its low side effect and interaction properties in comparison to some other NMDA antagonists such as ketamine, PCP, or DXM (already tried that one...not so good). However, noone (anywhere) seems to have tried any of the other such as Acamprostate or even Huperzine A, which after doing a bit of research, seems to put up quite a fight against Memantine and is much easier to get. Acamprostate is simply taurine that is able to cross the blood brain barrier, generally I'd say has a low side effect and contraindication profile, is available to get if you're able to get Memantine, and has the added bonus of being used to treat alcholism...but noone seems to be using it except for one guy I read about here on M&M. Although, I havn't done the research on it, I suspect that Acamprostate would not affect sleeping cycles or quality.

Again, read what I wrote about memantine's unique kinetics. Not all receptor antagonists are alike. Some are competitive, others uncompetitive; some have fast binding kinetics, others have slow binding kinetics; some have high affinity, others have low affinity; some are full agonists, others are partial agonists. And so on. Memantine is unique in that it is not a strong NMDA antagonist in conditions of low glutamate release. If it were, its NMDA antagonism would continually impair cognition.



Note also that strong NMDA antagonists without similar binding kinetics to memantine, like ketamine, are often used in models of schizophrenia. They so intensely inhibit PFC function and so prominently enhance mesolimbic activity that administration -- particularly chronic administration -- often resembles a schizophrenia-likes state.



Thus the receptor kinetics are the main reason to choose memantine. There are other factors, too. Ketamine's half-life essentially makes it worthless, regardless of kinetics. DXM has serotonergic affinities that limit its usefulness, it also suffers from a short half-life, and there are more concerns about toxicity. Huperzine A is incredibly weak by comparison to the other NMDA antagonits, lacks memantine's kinetics, and also is a strong AChE inhibitor, which is largely undesirable for many individuals. Acamprosate again alcks memantine's kinetics and, IIRC, has other undesirable receptor affinities.



But again, memantine's fast on/off kinetics are key. Another explanation for their importance, aside from avoiding the attenuation of low-concentration glutamate activity, is that other NMDA antagonists -- like ketamine -- have been implicated in causing neurotoxicity. IIRC, the mechanism for this has been accepted to be rebound excitotoxicity. In other words, they strongly inhibit NMDA, cause receptor upregulation, and as the drug wears off, excitotoxicity results due to hyper-sensitive NMDA receptors. Read up about Olney's lesions. Memantine is thought to avoid this both due to its receptor kinetics and, IIRC, due to its long half-life.

[Ex Dubio]

If you are looking for NMDA antagonism, neuroprotection, improvement in cognitive function, and low risk of side effects, huperzine A puts up quite a fight against Memantine.



Like I said before though, later on I found some evidence that Memantine could actually be the best choice for psychostimulant tolerance due to another property that it has. I will talk about that towards the end though.

Again, AChE inhibition is really not something most people want. You have also not taken into account the differing affinities of these compounds for the NMDA receptor. Magnesium is an NMDA antagonist, too, but I'd probably have to take a damn-near lethal quantity to get effects anywhere near memantine's. And there's still the receptor kinetics issue.

3) I have a bit of confusions with studies with NMDA antagonists and amphetamine/stimulants. Why do these studies say that a "reverse tolerance" occurs after repeated administration and an NMDA antagonist blocks this? These seem contradictory to what I thought usually happened when one repeatedly takes stimulant medications and drugs. Perhaps someone can help me.

This is referring to sensitization and is a very complex topic in itself. Suffice it to say that amphetamines have a peculiar property in which administration can cause increasing sensitivity to certain effects, possibly even while tolerance develops to other effects. It's a phenomenon noted in rodents and assumed to occur in humans, though its manifestations are unclear.



NMDA antagonism blocks sensitization through similar mechanisms in the mesolimbic system as those involved in tolerance.

Pretty much all of the studies in that first post there show the effectiveness of NMDA antagonists towards reducing tolerance (either general or a few different varieties of measures of the drugs effects such as stereotypy, locomotor activation, etc.) to those substances, except for the ones cited for stimulants. In fact, they are quite strange. Medievel does make a note here saying "unfortunately i found references regarding sensitization, it is established however that NMDA antagonists upregulate several dopamine receptors and it is backed up by many members that used it successful for stimulant tolerance".

Prevention of sensitization doesn't interfere with attenuation of tolerance, so it basically doesn't matter.

So, a "reverse tolerance" or strengthening of effects of the drug occurred when the rats were repeated exposed to the stimulants. In fact, this happened to three of the main effects usually observed from these stimulants in mice: locomotorstimulant, stereotypy, and convulsions. Then, the NMDA antagonist blocked this reverse tolerance effect. I tried researching this reverse tolerance phenomenon but it just confused me more. Perhaps someone can explain. Why would this contradict the theories and anecdotal reports around the web in a variety of ways? Perhaps when one translates these effects observed upon the mice into human terms, they are not necessarily the specific beneficial effects that a human is looking to achieve from use of amphetamines or cocaine and that they actually represent the exacerbation of side effects of the drug as is it is continually used. Or, perhaps a sensitization to these effects in rats and a blockade of the sensitization of these effects with an NMDA antagonist translates into the opposite in human terms. I'm not sure. Help

It doesn't contradict the theories. Sensitization is really a topic for another thread, but it is exactly what you describe. Increased responding to psychostimulants with repeated treatment. Obviously this doesn't occur with any of the major psychoactive effects of amphetamines in humans; we don't become more sensitive to the euphoric effects of amphetamines for example. But rodents seem to, at least using indirect measures of euphoria. As mentioned before, sensitization seems to manifest in some form in humans, but it's not entirely clear how.



In short, I'm just not sure that NMDA-induced blockade of sensitization is relevant to any human.

Once again mentions how repeated administration causes "sensitization" and how NMDA and AMPA metabotropic glutamate receptors participate in that.

Save this for another thread.

Once again this mentions the "reverse tolerance" effect produced after repeated administration. It says a little about NMDA antagonists; although it does mention how an "increase in arc" is inhibited by D1 and NMDA antagonists; it also highlights how a decrease in DA transporters could be related to "reverse tolerance" as well.

Again, note that reverse tolerance and sensitization are the same thing.

So, obviously I'm confused about this whole sensitization with repeated administration of stimulants in mice. I'm guessing it can be translating into humans as "tolerance" somehow. Someone explain?

It can't. Rodents also exhibit tolerance; it depends, IIRC, in large part on the dosing protocol. But the inference of sensitization in rodents to tolerance in humans is not right.

Then, there's a bunch of citations mentioning how NMDA receptors can help to upregulate DA (mostly this) and serotonin receptors in that post of Medievil's. As said in that last study there, DA transporters are related to "reverse tolerance". A few other abstracts along with a large consensus of the medical community and brotelligence seem to agree with this:

DAT being related to sensitization is discussed as a potential mediating mechanism; that said, D2 receptor upregulation is a better-accepted mechanism.

Chronic amphetamine: is dopamine a link in or a mediator of the development of tolerance and reverse tolerance? Kuczenski R, Leith NJ. Pharmacol Biochem Behav. 1981 Sep;15(3):405-13.

"Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism."



http://www.ncbi.nlm.nih.gov/pubmed/17608145

Dopamine receptor antagonists reverse amphetamine-induced behavioral alteration on a differential reinforcement for low-rate (DRL) operant task in the rat.

Cheng RK, Liao RM. Department of Psychology, Research Center for Mind, Brain, and Learning, National Cheng-Chi University Taipei 116, Taiwan, Chin J Physiol. 2007 Jun 30;50(3):149. Chin J Physiol. 2007 Apr 30;50(2):77-88.

"Together, these results suggest that the dopamine D1 and D2 receptors are involved and important to the temporal regulation of DRL response under psychostimulant drug treatment. Furthermore, this highlights the involvement of the brain dopamine systems in the temporal regulation of DRL behavior performance."



So, the Dopamine system is involved in the effects of stimulants and is one of the ways tolerance is modulated.

I mean, realize that what all psychostimulants do is increase mesolimbic DA. Tolerance to stimulants necessarily involves DA, because it essentially means an atteunation of mesolimbic DA response to repated administration.

[Taal]

Awesome, awesome, awesome. This cleared up a ton of holes for me and made me realize how my theories as well as many others I've come across for this have quite a bit of misconceptions in them as well.



Your explanations reaalllly filled in alot of holes and cleared up alot of the misinformed brotelligence I had been reading. I'm sure it helped many others too.



I'm glad you explained why Memantine was the best NMDA anatagonist for this job due to its kinetic ability to change its binding affinity and not act as a strong NMDA receptor antagonist when transmission is low, and strengthen when it becomes stronger in addition to explaining why the half-life was beneficial for the "tolerance prevention" rather than the "tolerance reversal" effects I (and probably many others had been hoping for and had misconceptions about. Lol, about the huperzine A, I just bought some too ;/



So, could there or has there been shown to be anyway to cause a quicker decrease in tolerance to amphetamines rather than just prevention by methods such as Memantine?



I'm still curious though and you didn't seem to completely answer this (or perhaps I overlooked it): Could Memantine perhaps be preventing tolerance due to its NMDA receptor properties by an action that effectively blocks part of the pharmacological mechanism by which amphetamine produces its desired user effects?



I do tend to have poor sleep quality ever since starting to take the Memantine, and my experiences you've already read.

What would you suggest to do to relieve this problem I'm seeming to have and be able to get better sleep?. Taking some melatonin the other night seemed to help with sleep quality (although not really getting to sleep). Here is generally my dosaging schedule:



Started about 9 days ago - these are all estimates.

Day1 ) .5 - some fogginess

Day2 ) .5 - less fogginess

Day3 ) .5 - even less fogginess - .5 more later that day

Day4 ) .5 and .5 later on that day

Day5 ) Jacked it up to 20mg - brain fog went up quite a bit and so did disruption in sleep aritechture

Day6 ) 20mg - brain fog same as day before quite a bit and disruption in sleep architechture

Day7 ) 20mg - brain fog same as day before quite a bit and so did disruption in sleep aritechture

Day8 ) 10mg - Decided to go back down - brain fog still there but not as strong

Day9 ) 10mg - brain fog still there but not as strong



May increase the dose the next day, but it looks like I really shouldn't. To me, after just making this it looks like I went up too quickly. The personal sleep problems Mematine seems to be disrupting for me are also bothering me quite a bit; in correlation with this I have noticed quite an increase in energy as well.



I'm not sure if you're done posting or not but I hope you comment on some of the other things I posted such as the NAC study with monkeys and elaborating on the alpha-7 antagonism...which I now understand my theories are quite off in regards to.





I may post more later. I'm starting to become quite tired from the diphenhydramine I just took.



By the way, do you have a citation handy showing Memantine's ability to change its strength/affinity of antagonism to the NMDA receptors depending upon the intensity of glutamate transmission? Then again, I guess just a result showing that it "regulated" glutamate transmission would be the same thing.

[MeDieViL]

I apoligize if this has been said before, but i'm feeling really scattered and unfocused so reading this whole thread is gonna be hard lol.



The reason memantine protects against mdma and amphetamine neurotoxiticy is because it inhibits their mechanism of action, however it does offer some protection because of the nmda antagonism but that is only partionally, most neurotoxiticy will still occur after the adaptation phase.

[Ex Dubio]

5) In looking at those studies I posted in that first post up there. They tend to allude me to ask this:

Can Memantine's neuroprotective effect when administered with MDMA or METH actually be attributed to a blunting of the desired effects one would take those drugs for anyway? A few statements up there lead me to believe this:

This is a good question, and I didn't know the answer offhand. To be clear, another way of phrasing the question is the following:



Does chronic, as opposed to acute, memantine show neuroprotection against amphetamine neurotoxicity?



The reason this is equivalent is that chronic memantine potentiates the effects of amphetamine. If chronic memantine treatment is also neuroprotective, then the mechanism of neuroprotection does not demand an attenuation of amphetamine effects.



I'm going to approach this from a different standpoint; we have five studies that discuss memantine, amphetamine, and neurotoxicity. Let's see exactly what each says.



1. (PMID: 17980434) Study conducted in vitro, which can be considered a model of acute dosing. Memantine prevented MDMA neurotoxicity through an alpha7 nAChR-dependent mechanism. Memantine did not attenuate MDMA-induced hyperthermia. Memantine prevented the MDMA-induced reduction in SERT. Increased glutamate activity is not associated with MDMA neurotoxicity.



2. (PMID: 18455739) Study conducted in mice, with acute administration. Memantine prevented 5-HT damange from MDMA and DA damage from METH. Memantine was more effective than a pure alpha7 antagonist, suggesting NMDA antagonism played a role. The memantine-induced reduction in ROS (from either MDMA or METH) was unaffected by NMDA antagonists and reversed by alpha7 nAChR agonists. A separate in vitro experiment found that MDMA-induced reductions in SERT were prevented by memantine, with similar results for METH. alpha7 agonism (?) by both MDMA and METH seems responsible for the decrease in transporter number. It appears MDMA is a competitive ligand of alpha7, whereas METH is a noncompetitive ligand, and memantine is a noncompetitive antagonist. Authors conclude neurotoxicity is prevented by preventing effects on transporters.



3. (PMID: 19897077) Study in vitro. An alpha7 nicotinic antagonist prevented METH and MDMA neurotoxicity in the form of ROS. Authors note that, in vivo, the same alpha7 antagonist prevents METH and MDMA neurotoxicity without affecting hyperthermia. Memantine prevented MDMA and METH effects on SERT and DAT, suggesting that the behavioral effects may be modulated by memantine. MDMA and METH are here noted to be both competitive ligands at the alpha7 nAChR. MDMA has higher affinity than METH. Interestingly, MDMA and METH induce up-regulation of the alpha7 nAChR with pre-incubation.



4. (PMID: 18582864) Study in rats, with acute administration. Memantine inhibited certain locomotor effects of MDMA, though also produced locomotor stimulant effects of its own. Memantine normalized memory aberrations that resulted from MDMA pretreatment. Memory impairment was also prevented by pre-treatment with memantine. Memantine alone actually improved the learning task.



5. (PMID: 20553881) Study in rats, with acute administration. Memantine pre-treatment recovered object discrimination that had been lost due to METH. Memantine pre-treatment also prevented METH-induced memory deficits.



OK, there are the five studies that looked at memantine and amphetamine in the same research. (4) and (5) are not relevant for neurotoxicity. None of these studies looked at chronic treatment. We can conclude:



-Memantine neuroprotection from MDMA/METH toxicity is almost completely mediated by alpha7 nAChR antagonism, though NMDA antagonism may play a lesser role.



-MDMA and METH are both alpha7 nAChR ligands themselves (presumably agonists), and memantine prevents their neurotoxicity by blocking binding to the alpha7 nAChR, thereby simultaneously attenuating the compounds effects on SERT/DAT.



-MDMA and METH, in the absence of memantine, bind to the alpha7 nAChR and induce consequent downregulation in SERT/DAT expression. The authors note that this is related to the MDMA/METH mechanism of action, but MDMA and METH have more effects than mere attenuation of SERT/DAT expression, so only some behavioral effects are likely attenuated by memantine. Moreover, memantine, when combined with MDMA or METH, attenuated certain behavioral effects, but not all behavioral effects.



-We have no data on the effects of chronic memantine administration on neuroprotection. Chronic memantine could induce extreme upregulation of alpha7 nAChR and thereby increase neurotoxicity, it could return to baseline and have no effect on neurotoxicity, or it could continue to decrease neurotoxicity. I see no data here suggesting one outcome is more likely than another.



It's still worth exploring amphetamine/nAChR interactions in greater detail. I find it odd that MDMA and METH upregulate the nAChR and yet their effects on both cognition and neurotoxicity are blocked by alpha7 nAChR antagonists, which likely also upregulate the nAChR. So now a little more discussion.



6. (PMID: 15715459) alpha7 nAChR agonists seem to reverse amphetamine-induced sensory gating deficits in rats.



7. (PMID: 15523001) Again, an alpha7 nAChR agonist reversed amphetamine-induced sensory gating deficits in rats.



8. (PMID: 12535854) d-amphetamine acts as a (partial?) alpha7 nAChR agonist in adrenal chromaffin cells.



9. (PMID: 11956948) Kynurenate levels, which are chronically decreased by amphetamine, is an endogenous alpha7 nAChR and NMDA antagonist.



10. (PMID: 18758759) alpha7 nAChR antagonists attenuate responding to amphetamine and nicotine in mice.



11. (PMID: 20890227) alpha7 nAChR KO mice are hyporeactive to the locomotor-stimulating properties of tranylcypromine and cocaine.



12. (PMID: 19741505) Chronic, but not acute, nicotine pretreatment enhanced METH-induced locomotor hyperactivity in mice, and this effect was attenuated by an alpha7 antagonist or an alpha4beta2 antagonist. alpha7 antagonism also attenuated some aspects of METH-induced analgesia.



13. (PMID: 17614110) In vitro, METH and MDMA displace binding of nonspecific nAChR ligands and alpha7-specific nAChR ligands. MDMA has a greater affinity than METH. MDMA and METH increased alpha7 nAChR binding as well as that of other nAChRs. Effects peaked at 48 h. MDMA was more potent. Enhanced binding seems to be related to increases in receptor number.



14. (PMID: 19187269) Kynurenic acid, a alpha7 nAChR and NMDA antagonist, reduces ACh release in the mPFC of rats.



15. (PMID: 19158670) An alpha7 nAChR partial agonist attenuates latent inhibition disruptions from amphetamine.



The above is essentially the extent of available research looking at amphetamine-alpha7 nAChR interactions, but it is unfortunately not particularly telling. What's odd is that d-amp, METH, and MDMA all seen to act as ligands at the alpha7 nAChR, and yet their neurotoxicity and behavioral effects are blocked by alpha7 antagonists while their cognition-impairing effects (at high doses) are blocked by alpha7 nAChR agonists.



Perhaps the amphetamines behave as partial agonists of the nAChR? But that may not explain everything. It's also again odd that MDMA and METH both increase alpha7 expression with prolonged treatment.



One final thought, bringing us back to memantine, is that we know alpha7 antagonists seem to attenuate the behavioral effects of amphetamines, whereas NMDA antagonists potentiate the behavioral effects of amphetamines. Given that the NMDA-dependent effects of memantine predominate in the long-run, we may be able to infer a fairly substantial extent of alpha7 upregulation.



Still, I think the necessarily conclusion in all of the above is that we don't have enough data to say much. I'm not even sure I agree with MeDeiViL's conclusion that memantine likely does not alter neurotoxicity in the long run, because we cannot rule out the notion that it decreases or increases toxicity in the long-run due to the paucity of data.

[Ex Dubio]

Working as a antioxidant...this is good. Reactive oxygen species probably don't contribute to desired user effects.



Hmmmm....perhaps MEM wasn't working as an antioxidant, it was just preventing the reactive oxygen species from ever being formed due to its alpha-7 nAChR antagonistic properties. Still...thats not necessarily bad for desired user effects.



Hmmmm....isn't MDMAs desired user effects thought to occur because of the decreased 5-HT uptake? That would mean it would blunt those effects.



Hmmmm....isnt amphetamine's desired user effects thought to partially occur because of an inhibition of dopamine reuptake?

No evidence AFAIK that memantine has any ROS scavenging ability, so I don't think at any point its acting like an antioxidant.



And desired effects of MDMA occur due to uptake of MDMA by SERT followed by binding to VMAT-2 and consequent "reversal" of the SERT. I've seen data that SERT is decreased with long-term use of MDMA, but I was under the impression that was a homeostatic response, not part of the actually effects.



Likewise, while METH does partially inhibit DA reuptake, it is much more potent at stimulating DA release, which is the dominant effect.

Well the hyperthermia effect of MDMA wasn't prevented my MEM, that would be awesome if it did.



But what if alpha-7 nAChR was one of the avenues that MDMA exerted its desired user effects? Fail.

It might be, but it's probably not the main mechanism. Also, hyperthermia of METH or amphetamine is only relevant at recreational doses.

So, correlating with alot of peoples advice, my personal account, and (some, but not all) anecdotal accounts Memantine actually may work as a neurprotectant simply by preventing MDMA or amphetamines (METH at least in these studies) from working properly and giving the user their desired effects.

It's possible. It's also possible that, regardless of memantine's effects on the subjective effects of amphetamine, chronic memantine simply does not afford neuroprotection. Upregulation of alpha7 with long-term memantine use may negative or otherwise modify the neuroprotective benefits.

Alluding to that last statement up there have to do with alpha-7 nAChR (under study #3):

MDMA and METH may have some similar pharmalogical mechanisms of exerting their effects since they are are kind of close relatives.

The results of those three studies examining the neuroprotective effects of Memantine do tend to show that this may be true in that they both somehow work through alpha-7 nAChR.

They both bind to alpha7 nAChRs and alpha7 nAChR agonism/antagonism can alter their effects. This doesn't indicate that they induce their primary effects through alpha7 binding, however.

The theories on the net seemed to point towards using NMDA receptor antagonists to reduce tolerance to the desired user effects of amphetamines by perhaps regulating the flow of glutamate and/or upregulating the NMDA receptors. Memantine was used for this purpose because it was an NMDA antagonist

that tended to have a low side effect profile, good safety, neuroprotective effects, antidepressant effects, and the added benefit of improving cognition in some individuals by, in theory, upregulating alpha-7 nAChR after the brain fog subided. Also, brotelligence echoed stories of its glory.

NMDA antagonists reduce the development of tolerance by attenuating net NMDA signal transmission in the mesolimbic system. But yes, much of this is probable, if rather unproven.

[Ex Dubio]

So, an additional mechanism by which tolerance to psychostimulants is modulated has to do with the nicotinic receptors. Now, these studies do say some confusing things to me too that hopefully someone can clear up, such as the first one that says "behavioural sensitization to amphetamine is associated with an up-regulation of the endogenous activation of nicotinic receptors".

Those studies say nothing about tolerance, and only sensitization. As I've said before, the relationship between the two is at least in part uncertain due to the lack of a good analogue for sensitization in humans. The study does note that behavioral sensitization to amphetamine involves an up-regulation of nAChRs in the NAc, but note that the up-regulation is specific to non-alpha7 subtypes, with a probable emphasis on alpha4beta2. This isn't really relevant to memantine at any rate.

Well, if we look at those other studies previously cited by Medieval about NMDA antagonism, they seem to indicate that "behavioral sensitization" or "reverse tolerance" can be prevented with an NMDA antagonist. Practically or anecdotally (at least at first glance), this seems contradictory - or maybe I just am interpreting it wrong, lol. So, in some way these phrases may translate to the "development of tolerance to the desired user effects" of these drugs.

It's not contradictory, again, because sensitization and reverse tolerance may not even be relevant to humans, or may only by relevant to certain dose patterns.

If that is the case, then study #2 reveals that a nicotinic receptor antagonist would help to prevent tolerance to some of the effects of psychostimulants. I believe that study #1 is also saying that but, to me, it seems to be saying the opposite (tolerance (they say "behavioral sensitization" would occur due to an up-regulation of activity?). Perhaps I am interpreting it wrong.

No, would prevent sensitization. Again, you cannot simply equate the two.

So, now, despite some of its side effects on sleep that I mentioned a long time ago, Memantine seems to be the perfect agent for reducing or perhaps preventing during co-administration (although this may blunt desired user effects) psychostimulant tolerance since it has both antagonism on the alpha-7 nicotinic receptors and NMDA receptors - both of which may be involved in the pharmacological mechanism by which psychostimulants exert some of their effects. This is assuming that the alpha-7 nicotinic receptors and the selective nature of Memantine's NMDA antagonism work on the same receptors that these psychostimulants interact with. This is also assuming that Memantine actually has an upregulating effect on these receptor systems.

Yep, this is why it's popular. But again, its tolerance-reducing effects are fairly definitively thought to stem from NMDA antagonism, not nicotinic effects. The reason for the confusion is, to be clear, that sensitization and tolerance are not the same thing.

However, two problems with this is that I still do not understand why one would ever take Memantine at the same time they took a psychostimulant, even after working up in dosage for a week or more and letting the "brain fog" clear as it would most likely blunt many (but perhaps not all) of the desired user effects. In addition to this, it seems that Memantine's half life is so long (40-60 hours) that one would have to wait a full 2-3 days or more before it is completely out of their system and would not antagonize the desired user effects of said psychoactive substances.

No. First of all, anecdotes should make it clear that taking memantine long-term along with amphetamine does not result in an attenuation of amphetamine's effects. This is due to one of two mechainsms. Either alpha7 nAChRs rapidly upregulate, resulting in near negation of memantine's antagonistic effects or memantine's NMDA antagonism "overpowers" the effects of alpha7 nAChR antagonism. My money is on the former explanation. Regardless, you have to take the NMDA antagonists at the same time as amphetamine; the whole point is that you want to block the amphetamine-induced increase in mesolimbic glutamate from activating NMDA receptors and thereby inducing tolerance.

6) Alright, last thing, I swear.



NAC is a really good idea to take with psychostimulants because it may provide two TOTALLY AWESOME benefits (Directly relevant study referenced below.):



1) Prevent neurotoxicity and associated damage by working as a very potent antioxidant when administered with amphetamines.

2) Preventing a reduction in dopamine transporter (DAT) cause by amphetamines in the stratium and perhaps in other areas amphetamines interact. This is awesome because various downregulations and changes in the DA system is thought to be one of the causes (in addition to potentially the nicotinic and NMDA systems) for tolerance to some effects of amphetamines as referenced by some of those studies way up there.

http://www.ncbi.nlm.nih.gov/pubmed?term=15199373

There's no evidence that NAC attenuates amphetamine tolerance. There is good evidence that it can attenuate the consequences of long-term cocaine use, however. And it does definitely protect, to some extent, against amphetamine toxicity. However, it has subjective effects that many find unpleasant; from my own experience, I'd describe its effects as not far from depression-inducing or at least anhedonia-inducing. It seems to have a substantial negative influence on mesolimbic DA function.



In short your (1) is correct, but you're misinterpeting (2). In (2), DAT expression is being used as a proxy for DA neuron survival. Saying that NAC attenuated DAT reductions is the same as saying that NAC attenuated DA neuronal death. After all, where is DAT expression? On DA neurons.



None of these relate to tolerance, however, and only relate to neuroprotection. For low-dose amphetamine, which seems to have uncertain toxicity -- if any -- I'm not sure how relevant NAC would be.

Hopefully and probably more than likely not, NAC doesn't block the desired user effects of psychostimulants with its neuroprotective mechanism of action. I'd say it has a lesser chance to than something that antagonizes one of the systems that they could directly work through (nicotinic or NMDA). Perhaps the full text would reveal the answer. Take your NAC with your Adderall, kids.



Alright I need to go do something more productive now.

Fairly sure NAC has no effects on NMDA or nAChRs, but perhaps you have evidence otherwise.



And try NAC before you suggest as much. It's a hell of an antioxidant for sure, but it has more subjective effects than you might think.



I believe NAC is thought to modulate non-NMDA glutamatergic circuits via an exchange pump, but I don't recall the details. Either way, I believe it may actually enhance amphetamine tolerance, but I'd have to go back and find references, and I unfortunately don't have time for that now.

[FunkOdyssey]

There's no evidence that NAC attenuates amphetamine tolerance. There is good evidence that it can attenuate the consequences of long-term cocaine use, however. And it does definitely protect, to some extent, against amphetamine toxicity. However, it has subjective effects that many find unpleasant; from my own experience, I'd describe its effects as not far from depression-inducing or at least anhedonia-inducing. It seems to have a substantial negative influence on mesolimbic DA function.

Big fat +1 on that

[Ex Dubio]

OK, more replies. This is exhausting, but these are good questions, and I get to learn some stuff. First, I'll take on some of the bolded material.

This sounds great but here is one of the problems I see with it. First off, you use the word "coadministration" which could perhaps be interpreted vaguely. Do you mean "take at the same time as amphetamines", "take a few hours after taking the first dose of amphetamines", "take when you crash from amphetamines", or perhaps "take on the days you don't take amphetamines"? This could have big implications for the efficiency of treatment - I know you have recommended the protocol to me in another post and in other posts on this forum of taking the memantine without amphetamines until the brain fog subsides (which is about a week or more sometimes) and then taking the amphetamine. However, in this summarization you have left that part out/vague with use of the word "coadministration." Additionally, I also find it vague as to what exactly to do after one takes that first dose of amphetamine after waiting for the brain fog to subside from Memantine. Do you continue to take it each day with the amphetamine or is there a different protocol? This next point would have big implications for that question.

With memantine, chronic administration is the norm -- acute administration has all the limitations discussed above. Given chronic administration, dose timing is completely irrelevant due to memantine's half-life. Yes, you take memantine at a steady (or upwardly titrated) dose for ~1 week with no amphetamine. Then you keep steady on your memantine dose and add amphetamine back in. You then stay on this combination indefinitively.

You say that Memantine "reduces abnormal neurotransmitter-mediated activation of the receptors." I am assuming that amphetamines would cause "abnormal neurotransmitter-mediated activation of the receptors." However, I would assume (just by general logic and also if you read those studies in the first post I made way up there especially the 2nd one) that amphetamine actually produces its subjective affects through the action of "abnormal neurotransmitter-mediated activation of the receptors." Therefore, if Memantine were to regulate this then it would also regulate the subjective effects of the drug on the user: a.k.a it would probably blunt the subjective effects. It could be one or any number and variety of effects the drug has on the user.

What he means is that memantine has a stronger antagonistic effect when synaptic glutamate levels of high. High synaptic glutamate can, to a limited extent, be thought of as "abnormal". However, the neurotoxic and subjective effects of amphetamines are not mediated through NMDA, as noted above. Instead, NMDA seems to somewhat selectively control mechanisms regulating tolerance and synaptic DA receptor expression.

Thus, in an oversimplified sense, if you were to take Memantine and amphetamines at the same time you would simply have two drugs counteracting each other and might not even get the "activational aspects of motivation" effects you're looking for in the first place. If amphetamine does indeed produce the subjective user effects (one of them or some number) at the molecular level in this fashion and Memantine antagonizes this, then of course neither excitotoxic neuronal damage nor desensitization would occur; but it would also be pointless to take the amphetamines in the first place.

Again, no. See previous posts for explanations of why. Also note that amphetamine-induced toxicity is not NMDA-dependent, or least not mostly NMDA-dependent. You have to understand that some effects are alpha7-dependent (inhibition of amphetamine effects, neuroprotection) and likely undergo rapid tolerance via receptor upregulation. Other effects are NMDA-dependent (attenuation of amphetamine tolerance) and do not have similar tolerance.

Now, there could be more details here or situations that I am missing and correct me if I'm wrong: for example, what if those diagnosed with ADD have abnormally low glutamate function. Amphetamines would increase this until it got to be too much and then Memantine put a cap on it: therapeutic effects are obtained without receptor damage or desensitization.

ADHD is weakly linked, IIRC, with elevated glutmatergic function in certain circuits, but given the hetereogeneity of ADHD, I suspect this is subtype-specific. Still, memantine attenuates amphetamine tolerance seemingly irrespective of underlying pathology.

Additionally, perhaps the NMDA antagonism/gluatamate transmission regulation would sensitize this system to amphetamine's pharmacological mechanism through upregulation or something else...I'll talk about that in a bit.

No, NMDA antagonism -- in the extreme -- is a model of schizophrenia, just as is chronic high-dose amphetamine administration. NMDA antagonism actually potentiates the effects of amphetamine, in addition to preventing tolerance, though the former effect is likely to be slight at typically used doses.

Although this is subjective (and somewhat nit-picky on my part), Memantine is very well tolerated if you compare it to some other options for NMDA antagonism such as Ketamine, DXM, PCP, etc. But, that IS definitely on a person by person basis. The experiences I have read of people having with it do vary quite a lot. For instance, some note that the brain fog never really went away even after the suggested time frame of a week - and even then experiencing crazy brain fog (even if it eventually goes away) isn't my favorite side effect.

This may vary from person-to-personal for reasons that are not yet clear, but may be related to other drugs being taken at the same time.

There could be better alternatives for NMDA antagonism out there such as Acamprosate and perhaps especially Huperzine A (look at those studies I posted way above). Then again...these arn't as anecdotally tested on the internet for this purpose.

See discussion above for theoretical reasons why not.

Right here I'm really wishing that the phrase "without blocking subjective therapeutic effects" was added and then there was a solid citation after it so everyone's amphetamine tolerance issues could be easily and simply solved - but alas this is not here... ...).



I will say that in this last paragraph you hint at the idea of perhaps not doing a "by the book" co-administration and taking it on the off days with the hope that it would increase the rate at which tolerance to the desired therapeutic effects faded away.

Already explained why subjective effects are not blocked, but more practically speaking, do you think the memantine and amphetamine combination would have gained any traction on the internet if memantine blocked the subjective effects of amphetamine? If that were the case in the long-run, no one would care or otherwise advertise the combination.

Now, I am presuming (as I have stated before) that the current theory is to take the Memantine or said NMDA antagonist on amphetamine off days in the hopes that it will more quickly sensitize that system to one of the pharmacological mechanisms by which amphetamines produce their desired effects.

No. Aside from the fact that memantine's half-life would make the entire idea behind this foolish, we're trying to block NMDA activation, not enhance it. Taking amphetamine during withdrawal from an NMDA antagonist would enhance tolerance by increasing NMDA activation. The point is to take them together.

There are a three more main points I want to make in regards to your writing:



1) Is it actually proven to upregulate this system?:

Although I feel and probably sound quite lazy when I say this (I could probably prove myself wrong here when I say this), is it really proven that Memantine will actually upregulate/sensitize-to-amphetamines/restore the glutamate function/NMDA receptors? Does it do this through permanent structural changes or only temporarily while the drug is in the system? Does anyone have a citation for this? In theory it would be true, but has it been shown to?

The research on this stuff is just incredibly recent -- you can only expect so much. The anecdotal reports overwhelmingly support this idea, I'll tell you that much. Moreover, you even quoted some of MeDeiViL's citations pointing to increased D2 expression in the striatum with NMDA antagonist treatment. The citations are in several threads on memantine and NMDA on this board, though they are largely indirect; for example, many citations show memantine (or NMDA antagonists) increase the effects of amphetamine or increase striatal D2 expression or increase mesolimbic DA release. This is as close as you'll get to proof, given how little research has been done on NMDA/amphetamine interactions.



Continued in the next post.

[Taal]

Awesome. Through Ex Dubio's correction of everything I posted, I think the general understanding and clarification (at least I hope - and perhaps only in regards to me) of this topic is going way up. This is pure gold to me.



I'm glad you all (Ex Dubio and FunkOdyssey) mentioned your experiences with NAC. To be honest, I do not have much experience with that supplement. He also pointed out my misconceptions about it, which were important:

In short your (1) is correct, but you're misinterpeting (2). In (2), DAT expression is being used as a proxy for DA neuron survival. Saying that NAC attenuated DAT reductions is the same as saying that NAC attenuated DA neuronal death. After all, where is DAT expression? On DA neurons.

Unfortunately, I just went out and bought some before you posted that, haha. Oh well..



Plan on posting more later, a lot to digest and think about.

[Ex Dubio]

2) Practical application of this method with the Memantine's half life:

Let's say that Memantine is able to upregulate the glutamate NMDA receptor system and decrese their tolerance to desired effects. Let's also say that Memantine blunts these beneficial effects through its NMDA receptor antagonism. You wouldn't want both to be in your system at the same time: that could be counterproductive. This would become especially difficult to manage since Memantine's half life is listed as 60-100 hours on (at least on Wikipedia it says that). Perhaps it excretes faster than that, perhaps the NMDA receptor antagonism isn't active the entire time, or perhaps there are ways to eliminate it faster (one erowid report suggested drinking a ton of cranberry juice).

The point of using memantine is to reduce NMDA signaling. A consequence of NMDA antagonism is NMDA receptor upregulation, but this upregulation does not nullify the effects of NMDA antagonism. So long as memantine is being taken, NMDA signaling is reduced from baseline. The point is that NMDA activation is in large part responsible for tolerance.



Also again, memantine potentiates behavioral effects through NMDA antagonism. It only inhibits subjective/behavioral effects through alpha7 antagonism. Note that, in contrast to NMDA, nicotinic receptors undergo an unusual kind of upregulation that can -- in some cases, IIRC -- result in nullification of the effects of the original compound. There's not a lot of good data here, but let me explain.



Baseline signal strength of alpha7 nictoinic and NMDA is 100 and 100. After a day of memantine, before receptor upregulation, signal strength is 50 and 50. After a few weeks, NMDA partially upregulates, resulting in a signal strength of 80. alpha7, however, fully upregulates, resulting in a signal strength of 100.



These numbers are pulled out of thin air, so ignores their magnitudes; the point is that, when a receptor antagonist is applied, most receptors upregulate. The degree to which they upregulate varies, however. In the case of nicotinic receptors, I seem to recall them being able to upregulate to the point of nearly nullifying the effects of an antagonist, at least in some circumstances. For NMDA, this is almost certainly not the case.



Note that it may be that alpha7 does not fully upregulate, but that NMDA antagonism's potentiating influence on amphetamine-related behaviors simply nullifies any effects of alpha7 antagonism.



Suffice it to say, no one is arguing you want memantine out of your system before taking amphetamine.

3) Other mechanisms at work that could be effecting tolerance/adaptations to amphetamine's subjective effects:



What about treatment for these in addition to other avenues of doing so? These should be looked at too!



Although all of these systems are generally interconnected, there are other parts of it that could be focused on and treated as well. I talk about this in my mega-post. The predominate systems seem to be, at least to my understanding: DA neurons/system, the NMDA neurons/system, AND the nicotinic acetylcholine neurons/system. I have not really seen the nAChR really mentioned yet in regards to this topic. I talk about this last one at the end of my last post with citations. Here they are again anyway:

No, again sensitization and tolerance are not the same thing. There's no evidence presented above that nAChRs are involved in amphetamine tolerance. That's not to say they don't play an important role in mediating amphetamine's effects, but they do not seem to in any way modulate tolerance. People haven't talked about other ways of attenuating amphetamine tolerance because there really aren't any effective means that we know of.

Eur J Neurosci. 2004 May;19(10):2859-70. "Long-lasting nicotinic modulation of GABAergic synaptic transmission in the rat nucleus accumbens associated with behavioural sensitization to amphetamine." de Rover M, Mansvelder HD, Lodder JC, Wardeh G, Schoffelmeer AN, Brussaard AB.

J Neurosci. 2002 Apr 15;22(8):3269-76. Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ. "Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation."



You seem to focus predominately on the NMDA neurons/system, which, admittedly, as you say effects the DA neurons/system too (hell, they are all interconnected).

Again, sensitization is not tolerance.

But what about other avenues and thus treatments that could supplement this (such as nADhR antagonism)? What about ones that may not block the beneficial effects of amphetamines when administered at the same time (such as NAC - discussed above and below)?

nAChR antagonism is what blocks the behavioral effects of amphetamine when administered at the same time. NMDA antagonism isn't. And again, there's no evidence I've seen that nAChR is involved in tolerance either.

The nADhR system and how it seems to have strangely been overlooked:



Luckily, and quite ironically (or is it?) Memantine has alpha-7 nADhR upregulating properties due, in theory, to it's alpha-7 nADhR antagonism. I will admit here that the specific type of nADhR antagonism that Memantine has, "alpha-7", may not be the correct form to actually sensitize the nADhR system to the pharmacological mechanisms of amphetamine in producing its desired effects; perhaps this is an overgeneralized theory. Who knows.

alpha4beta2 is more closely involved in amphetamine sensitization, yes. But this is not even relevant to the topic at hand.

Regardless, this thought is very peculiar to me (in fact, this makes me think I may be missing something and completely wrong about this part):



The general consensus in addition to your advice seems to be to wait until the "brain fog" from Memantine is alleviated. Although there is slight ambiguity around here, this is more than likely or mostly (if it were to be a combatination of the NMDA and alpha-7 nAChR antagonism) due to Memantine's alpha-7 nADhR antagonism

(Aracava Y, Pereira EF, Maelicke A, Albuquerque EX (March 2005). "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 312 (3): 1195–205. doi:10.1124/jpet.104.077172. PMID 15522999.).



In a beneficially ironic way, waiting til the "brain fog" dissipates would signal upregulation of the nADhR system and thus perhaps tolerance reduction to the subjective effects produced by amphetamine's pharmacological action with these receptors.

The explanation for why one would wait to take amphetamine only after a week or so of memantine has nothing to do with brain fog -- which should attenuate regardless of whether amphetamine is present or not due to alpha7 upreegulation -- and everything to do with memantine's ability to inhibit, but not reverse, tolerance, at least at normal doses.



But again, there's no tolerance reduction related to alpha7 here.

However, I do not remember (correct me if I'm wrong or missing something) anyone mentioning this anywhere. You do not seem to mention it in your summarization anywhere. It just seemed to remain overlooked. Also, it may be too big of a generalization/assumption to believe that the specific alpha-7 nADhR antagonism will sensitize the entire system to amphetamine's pharmacological mechanism of action.



Thus, perhaps Memantine's primary tolerance reduction properties to the subjective effects (or certain specific effects) of amphetamines could be attributed to it's alpha-7 nAChRs antagonism in contrast to its NMDA receptor antagonism and glutamate regulation abilities.

The problem is that sensitization is not something you want or want to avoid, because in humans it just doesn't work the same way as in rats. In rats, you give them amphetamine a couple times, wait a week, and give them amphetamine again, and their locomotor response is greater than it was the very first time they were given amphetamine.



Now, MeDeiViL says he's experienced something like this, and it is possible that it occurs in humans, but there's no evidence for such an effect. Moreover, sensitization typically only occurs when a drug is first introduced and is semi-permanent thereafter. Even if it does occur in humans, it just doesn't seem relevant to the conisderations here. To my knowledge, sensitization can also not be continually potentiated, so there's not a great deal of control that can be exercised there.



Finally, there is some notion that sensitization is associated with pathological changes in rat brains associated with addiction, making it potentially undesirable.



If you read enough studies about sensitization your rapidly gain the notion that it's not understood well even by the researchers investigating it. Whether it occurs in humans is still unclear and what its ramifications are for therapeutic drug use are likewise unclear. All that seems established is that it is not a phenomenon that opposes tolerance and that it cannot, according to any known research, be manipulated to continually increase responding to a drug.



In short, sensitization is a poorly understood phenomenon with an incredible amount of complexity behind it and with uncertain cross-species generalization. I'd caution against trying to draw conclusions of any kind of from studies on sensitization, as I'm just not convinced you can appropriately justify such results.

Then again, having both properties (NMDA receptor antagonism and alpha-7 nADhR antagonism) probably doesn't hurt; although it probably increases the likelihood that it would block or blunt (or maybe even change in some way) the subjective beneficial affects when administered simultaneously with amphetamine.

Technically, most of the research seems to suggest that a pure NMDA antagonist with similar pharmacological properties would suffice as well or better than amphetamine.

And now for a supplemental, healthy, non-blunting-to-desirable-effects, easy, practical, accessible, completely legal, and very-tolerable way to attenuate that tolerance you get to the -oh so sweet- desirable effects of amphetamine in addition to preventing damage to your dopamine system!:



NAC.



NAC may also attenuate tolerance to the beneficial effects of amphetamine.



I referenced one study in my previous post I was very excited about that I wanted to mention again:



"Protective Effects of N-acetyl-L-cysteine on the Reduction of Dopamine Transporters in the Striatum of Monkeys Treated with Methamphetamine."

Neuropsychopharmacology. 2004 Nov;29(11):2018-23.

Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M.



This study discusses the results of treating monkeys with the antioxidant NAC while they were administered METH which "significantly attenuated the reduction of DAT". Theoretically, attenuating the reduction of DAT could help keep the beneficial effects of amphetamines going too!

Already responded to this study in a previous post, but I want to reiterate that the study found that NAC attenuated neurotoxicity from high-dose METH treatment. It attenuated decreases in DAT by attenuating DA neuronal death, nothing more. This does not point to any effects of NAC that would lead to tolerance reduction.