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NMDA antagonists for drug tolerance, does it work?


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#31 someidiot

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Posted 17 October 2010 - 12:23 AM

Welp, I bought about 14 bucks of this stuff before doing my homework so I'm scouring my library's database (or internet) for innocuous uses; just for heuristics:

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

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

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Posted 17 October 2010 - 12:26 AM

Supposedly it is also good as an anti-obesity agent. It helped curb binge eating in fat folks by inhibiting glutamate. I have the abstract if any are interested.

...uggh, i smell something kindred to 'stupidmax' (topiramate)

Econ Hum Biol. 2005 May 7; [Epub ahead of print] Related Articles, Links

A new anti-obesity drug treatment: First clinical evidence that, antagonising glutamate-gated Ca(2+) ion channels with memantine normalises binge-eating disorders.

Hermanussen M, Tresguerres JA.

Aschauhof 3, 24340 Altenhof, Germany.

The regulation of appetite relies on complex hypothalamic neurocircuitry of which the arcuate nucleus, and the hormone leptin play important roles. Arcuate nucleus neurones are essential for the regulation of eating behaviour, but they can be intoxicated by elevated serum levels of the amino acid glutamate (GLU). Neurotoxic effects of GLU are mediated by the N-methyl-d-aspartate receptor (NMDA-R). But the neurotoxic effects of GLU can be prevented. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent non-competitive NMDA-R antagonist, antagonises GLU-gated Ca(2+) ion channels and completely prevents the adverse effects of GLU. Also the non-competitive NMDA-R antagonist memantine displays neuroprotective properties. In view of a previously published hypothesis that human obesity results from chronic over-consumption of GLU, we performed a therapeutic trial in five obese, but otherwise healthy women. Memantine treatment markedly decreased appetite within few hours and complete suppressed the binge-eating disorder within 24h. Body weight decreased markedly within a few days. The findings strongly support the hypothesis that elevated levels of nutritional GLU play an important role in the pathomechanism of human obesity. We suggest to treat human obesity by protecting the hypothalamic signalling cascade of leptin action with low to moderate affinity, non-competitive NMDA-R antagonists that selectively block the GLU-gated Ca(2+) ion channels.

I'm guessing memantine dissociates subjects from interoception?

Edited by someidiot, 17 October 2010 - 12:55 AM.


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#33 aLurker

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Posted 17 October 2010 - 12:33 AM

Post everything, I don't care about losing weight at all but I'm intrigued by memantine in general.

Edit: k thanks

Edited by aLurker, 17 October 2010 - 12:54 AM.


#34 someidiot

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Posted 24 October 2010 - 08:00 PM

Itz abouts dat time againzz!

(2005)

Effect of memantine on the a7 neuronal nicotinic receptors, synaptophysin- and low molecular weight MAP-2 levels in the brain of transgenic mice over-expressing human acetylcholinesterase

Transgenic mice over-expressing human acetylcholinesterase (hAChE-Tg) display memory impairments, cholinergic deficits and reduced dendritic branching. In this study, we found a reduced number of N-Methyl-D-Aspartate (NMDA) binding sites and reduced levels of low molecular weight (LMW) microtubule associated protein 2 (MAP-2), in addition to an increased number of 4 and 7 nicotinic receptor (nAChR) binding sites in the brain of hAChE-Tg mice. Treatment with memantine, 20mg/kg/day during 14 days, significantly increased the number of [125I]bungarotoxin (7 nAChR) binding sites in the frontal- and retrosplenial cortex of hAChE-Tg mice and synaptophysin- and LMW MAP-2 levels in the cortex of both hAChE-Tg and FVB/N controls. The findings reveal an alteration of the glutamatergic system in hAChE-Tg mice. Whether the effect of memantine on 7 nAChRs, synaptophysin- and LMW MAP-2 levels is a direct effect, or an indirect effect via the NMDA receptors, has to be further evaluated.


(2004)

No nerve growth factor response to treatment with memantine in adult rats

Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimers disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.
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#35 someidiot

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Posted 24 October 2010 - 08:22 PM

Link to full text (2007)

Memantine fails to facilitate partial cigarette deprivation in smokers – no role of Memantine in the treatment of nicotine dependency?

#36 ultranaut

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Posted 25 October 2010 - 06:42 PM

I've been playing around with various things to mitigate amphetamine tolerance.

Huperzine A seemed to help but it also put me into an unpleasant semi-angry mood. I am going to try it again eventually, but it will have to be during a time when I can consistently be alone for a few hours after taking it.

DXM helped somewhat, but I take bupropion so I am extra sensitive to it and can't really take more than 60mg without feeling like I'm on E. Many years ago (before bupropion) I took DXM recreationally on a fairly regular basis, back then 60mg had no effect, and I weighed less. Now that I think about it, I should really test this one out more.

Magnesium seems to help quite a bit, it's what I've currently settled with. It seems to help end the amphetamine effects faster, I take it an hour or two before bed on days when it feels like ambien just won't be enough to knock me down. Taking it daily while on a break from the amphetamines seems to lessen the amount of time necessary to reverse tolerance. I've had no noticeable side-effects.

There's no NMDA effect to this that I'm aware of but I've found that taking P5P seems to help slow down the development of tolerance. It definitely helps prevent that horrible "fuck I am strung out on amphetamines and need a break" feeling that happens when you crash. I take some every morning around 7am and most nights around 7pm. I imagine it as fuel for the fire, gotta keep those neurotransmitters from getting too depleted. The only side-effect I've noticed is if I take a dose at night I tend to have weird and often fucked up dreams. The later I take it the more likely it is to happen so it seems to pretty clearly be the P5P.

Something else that seems to really help: Mix up the doses. Instead of taking 20mg each morning and 20mg more with lunch some days take 10mg when you wake up, 10mg more a few hours later, and then 20mg at lunch, other days take 30mg when you wake up and 10mg in the early afternoon. Take less some days, skip doses. You get the idea. I'm not sure why this should make a difference but I am convinced that it does. I used to try to be regimented in my dosing, same amount at the same times. Skip at least x days per week. I take less overall now and it's more consistently effective.

#37 medievil

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Posted 25 October 2010 - 06:48 PM

Have you considered memantine isntead of DXM? It lacks recreational effects and also many side effects that DXM has.

#38 ultranaut

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Posted 26 October 2010 - 09:36 PM

Have you considered memantine isntead of DXM? It lacks recreational effects and also many side effects that DXM has.


I have, it's definitely on my list. If it were easier and cheaper to buy some I would of already tried it, it's just not a high enough priority right now.

#39 medievil

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Posted 26 October 2010 - 09:40 PM

Its dirt cheap if you order from alldaychemist.

#40 medievil

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Posted 26 March 2011 - 09:34 PM

http://www.bluelight...ad.php?t=501875

More experiences can be found there.

#41 jadamgo

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Posted 31 March 2011 - 04:29 PM

I'd like to draw more discussion to amantadine. Since people usually get prescribed AMP for ADHD, amantadine might work better than memantine. After all, amantadine is a dopamine agonist, and it's sometimes prescribed off-label by ADHD experts for 24-hour "nonstimulant" symptom control. It works better than strattera but not as well as AMP or MPH (in responders to those stimulants, obviously).

Maybe taking amantadine daily and also taking AMP either daily or as needed for stronger symptom control is a winning strategy for ADHD.

I don't currently have time to pull up any more studies on amantadine, but my source for claiming that it's used as monotherapy for ADHD is "Delivered from Distraction" by Hollowell and Ratey.

#42 August59

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Posted 12 November 2013 - 11:51 PM

I know this thread is a little old, but the question seems to pop up quite often. It's of interest to me because of my Adderall tolerance. This is actually an older post from another forum, but I have ran across bits and pieces of different studied that support most of it.

The one that I don't quite get is the magnesium as I thought the only form of magnesium that would cross the blood brain barrier was the magnesium L-threonate, but it seems to be brought up very frequently.





I recently changed from adderall to dexedrine, and let me tell you the high you get from dexedrine is much much cleaner, and it feels so much better then adderall. But, tolerance is an issue I was lookin around and found this in another forum.

Almost everyone's opinion on using speed/amphetamine/meth is that the best highs were the first two (or three). That is also the case with me.

When I first tried speed I've used very small amount (I'd say it was around 50 mg) of rather pure amphetamine and damn, it was the best day of my life :] I remember that I was euphoric for around 12 hours, I couldn't stop talking, the music sounded extremely well, I was full of motivation and never felt better in my whole life. Afterwards I had no comedown.

My second attempt wasn't as fantastic, but also wonderful. Since then I've never achieved that extremely euphoric sensation with my head tingling from pleasure and my insides screaming "DAMN I FEEL FUCKING AWESOME!!!". After a year of my speed usage and trying doses even four times as high as the 1st amount I tried - I never came close to that feeling. Sure, I can be motivated, energetic, have a great time during the tweak, be very sociable, but it is still not like during the first two times. I'm aware that amphetamine tolerance develops very quickly and stays at that level for a long period of time (even when taking breaks), so lately I've been doing some online reading on that subject.



Amphetamine tolerance is caused by excess Ca++ influx through the NMDA receptor gated calcium channels on the outer membranes of the dopamine cells bodies in the ventral tegental area, one of two areas in the brain with concentrations of dopamine producing neurons.

As alluded to above, taking an appropriate NMDA (partial) antagonist will prevent the development of a tolerance for the effects of an amphetamine or amphetamine-like stimulant. Also, by preventing excess Ca++ influx into the neuron, an NMDA antagonist will prevent associated brain alterations and damage (excitotoxicity).



Studies have indicated that amphetamine tolerance is prevented by exogenous or endogenous agents that are able to inhibit excess Ca++ influx into the neuron through the gated calcium channels on the neuronal membrane that have NMDA subtype glutamate receptors.Glutamate , the body’s major excitatory neurotransmitter, opens the gated calcium ion channels upon attaching to the NMDA receptor. A number of other receptors are also expressed on these calcium channels, which, when stimulated, either facilitate or inhibit glutamate’s action.



It is also important that agents that inhibit calcium channel activity not also cause deficient Ca++ influx. For example, ketamine is a full NMDA receptor antagonist, that prevents excess Ca++ influx and amphetamine tolerance. But being a full NMDA antagonist, ketamine in excessive doses results in deficient Ca++ influx. This could be one of the reasons it leaves K-user in a state of disassociation.



So basically we have following NDMA antagonists:

1. Memantine (Akatinol/Axura)

2. Acamprosate (Campral)

3. Amantadine (Symmetrel/Amantix)

4. Magnesium (supplement)

5. Dextrometorphan/DXM

6. Ketamine

7. PCP

(funny that 5,6,7 are recreational drugs)



Two of them have minimal (or none) side effects and have been identified (and verified by one anecdotal person, which has been taking amphetamine-type stimulants and NDMA antagonist with same beneficial effects for a period of 2 years) as preventing amphetamine tolerance: 1) Memantine and 2) Acamprosate.



1) Memantine is a partial NMDA antagonist that effectively puts an upper limit on Ca++ influx without compromising healthy levels of Ca++ influx. Memantine is not available in the US at this time. It is in stage 3 trials for Alzheimer’s disease. US approval may come within the next 2 years. Memantine is now approved in the European Union for the treatment of Alzheimer’s. It has been marketed in Germany since 1978 for the treatment of dementia and other cognitive disorders. It comes in 10mg tablets. One or two tablets/day are sufficient to prevent amphetamine tolerance, overactivity of the NMDA receptor and consequent free radical stress inside the neuron. The most expensive option though.



2) Acamprosate (n-acetyl-homo-taurine) analogue of the amino acid taurine. Alternatively, it may be termed as a carrier molecule for taurine, that allows taurine to readily cross the blood brain barrier, unlike taurine itself. Taurine is a NMDA receptor antagonist. Acamprosate is an investigational drug in the US, undergoing stage 2 (?) trials for the treatment of alcoholics. It is available in most European countries as a treatment for alcoholism, with great efficiacy. Cheaper than memantine, however efficiacy should be the same.



3) Amantadine, originally used in the treatment and prophylaxis of influenza infection and drug-induced Parkinsonism, also blocks NMDA receptors. Besides it is beneficial in traumatic head injury, dementia, multiple sclerosis,cocaine withdrawal and depression. Amantadine appears to act through several pharmacological mechanisms, none of which have been identified as the one chief mode of action. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels. I couldn't find what amount of the drug should be used to block NDMA. Cheaper than Acamprosate. No one has tested it yet, but I think it would be a good choice.



4) Magnesium is also an NMDA antagonist. Most people are deficient in magnesium, and stress reduces magnesium levels. Whether or not one takes amphetamines, magnesium supplementation is very important for mood, general well-being and keeping stress levels under control. It is also important to take magnesium in efficient form, with adequate bioavailability. The best type is magnesium glycinate (chelated) with bioavailability at around 80%. Second best is magnesium carbonate with (I don't remember exactly) bioavailability at little above 30%. Supplemented magnesium should be at 500 mg/day level. Also there is a study which shows that children who use amphetamine-type stimulants have bad magnesium/calcium balance. Calcium levels stay the same with amphetamine usage, but magnesium levels drop.



5) DXM - definitely the cheapest option of all NDMA antagonists, but I'd rather use Memantine or Acamprosate. Although, I've heard anecdotes that doses as low as 70 mg/day are enough to block NDMA - I couldn't find those amounts in abstracts/studies.



6) and 7) I wouldn't use as an amphetamine tolerance prevention. Ketamine for its known effects (you wouldn't want to be in a K-hole during the tweak just for the sake of prevention tolerance)

PCP - this one doesn't need explanation. It has nasty side-effects and I've mentioned it just because it is a NDMA antagonist. I wouldn't touch it even if it was dirt cheap.



Does anyone know if this stuff would really work? If not how long does it take for your tolerance to speed/amphetamines to go down without taking any of this stuff?


Read more: http://www.drugs-for...9#ixzz2kTeR4luA

I hope this provides some good information and/or fosters some good conversation on this topic as there may be some new information available due to new nootropics, vitamin/mineral formulations and medications available that may provide even better benefits for amphetamine and opiate tolerance???

Thanks

#43 riloal

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Posted 13 November 2013 - 02:31 PM

I,m going to test amantadine soon. I used memantine in the past for prevent my tolerance to ritalin,it worked but after two years stopped to work, so now i will try amantadine.
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#44 MrSliz1724

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Posted 17 March 2014 - 02:04 PM

Bump for discussion

#45 Mirage

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Posted 02 March 2016 - 05:49 PM

++ bump for discussion. Very interesting topic. If someone has a practical experience with reducing tolerance to stimulants - please share.



#46 BobbyDick

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Posted 02 March 2016 - 07:42 PM

nAchRs antagonism have bigger impact to reverse tolerance than NMDA antagonism.
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#47 Mirage

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Posted 02 March 2016 - 07:54 PM

nAchRs antagonism have bigger impact to reverse tolerance than NMDA antagonism.

Tell us about your experience with them then.



#48 truboy

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Posted 03 March 2016 - 03:50 AM

Not stimulant, but magnesium citrate helped me reduce tolerance to piracetam.

#49 BobbyDick

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Posted 03 March 2016 - 05:25 PM

Nicotinic receptors control all or almost all neurotransmitters in a direct way. You could say that the stimulation of nAChRs provides the most natural for the brain boost all neurotransmitters.

Generally, the most important are the nicotinic receptors which control level of sensitivity of receptors and the rate of formation of new neurotransmitters and their level of ejection. Unfortunately, persistent stimulation of theirs is only a temporary solution because beyond desensitization of the receptors is also created "downstream tolerance", which tolerance isn't formed at the level of themselves receptors but only at the level of the effects of further stimulation. NAChR antagonists as MXE, DXM or Ibogaine seem to prevent downstream tolerance

 

How blockade of nicotinic receptors affects to the other neurotransmitters?

 

Reduces or even completely block their ejection. For example, when nAchRs are blocked, it's extremely difficult to achieve euphoria, indicating that blocking dopamine ejection. For this blocking these receptors results in anhedonia, amotywation, depression and psychotic symptoms. Just remember the worst exit after any euphoric drug (eg. Mephedrone) and these are the symptoms of a strong blocking nicotinic receptors.

 

 

D1 and D5 agonists (eg. Dopamine) cause an increase in ejection ACH and thus cause the stimulation, increase motivation and euphoria. NAChR agonists cause upregultion (increasing the quantity of ligand binding), and desensitization (reduced sensitivity of ligand binding) receptor. MXE reverses the desensitization and at the same time accelerating upregulation receptors. Through this mechanism disociants work antiadiction and refrain build or even lower tolerance for all drugs."
"In general, the negative effects of the stimulant related to their effects on the cholinergic system. First, to big agonizing leads to partially block receptors and thereby created neurotoxicity, further drug use leads to nAChRs desensetization and creates long-term mental deficits among users (attention deficit disorder, anxiety, phobias, psychosis, addiction). Generally, MXE counter both these phenomena.

 

 



#50 medievil

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Posted 04 March 2016 - 04:09 PM

I made one big thread about this in the advanced section of bluelight with what i would say i 90 or 95% succes rate, a thread i made in the general drugs subforum had more negative reports indicating that ppl where it does not work for simply do not post their results, so i cant say exactly for how many people this will work, its not the golden bullet that works for 100% of all individuals but definatly for most people, also ppl report needing differened mem doses, more succes with dxm etc which will play a role.

 

Also with this post i would like to absolutely encourage ppl this intervention doesnt work for to report back, this could be due them maybe having more succes with another nmda antagonist or a differened subgroup of chemicals. we need real life results, and im not someone that pushes things i beleive that work so will work for everyone.



#51 Mirage

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Posted 09 March 2016 - 05:31 AM

Yes, medievil, I've read this whole thread on bluelight. It was very helpful, thank you very much for creating it. Too bad its archived now so I can't bump it for a further discussion.

 

I started taking DXM last week myself to help me with tolerance to dexedrine, ritalin and modafinil(all are stimulants that act through dopamine and adrenaline release). I started with 30 mg per day and yesterday I took 50 mg at the morning and 30 mg in the evening. Yesterday was also the first time I took a stimulant(dexedrine) with DXM. What I noticed was a noticeable potentiation of dexedrines effects AND potentiation of its side effects. Particularly, the tachycardia - it was stronger and much longer than usual. Had to take high doses of beta blockers to counteract it.

 

So I'm wondering whether this is just a temporary effect as my body adjusts to DXM or is this to be expected and I should somehow adjust my DXM dosages/regimen or maybe it's something else. And I'm taking a short-acting HBr version of DXM as Delsym is not available in my country.


Edited by Mirage, 09 March 2016 - 05:58 AM.


#52 Galaxyshock

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Posted 11 March 2016 - 11:43 AM

Do NMDA-antagonists work for benzo tolerance?



#53 medievil

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Posted 12 March 2016 - 11:54 AM

Do NMDA-antagonists work for benzo tolerance?

Alot of anecdotes say they do yes:) the dose you need is differened for everyone tough, it can be up to 40mg.



#54 sativa

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Posted 12 March 2016 - 07:53 PM

Do NMDA-antagonists work for benzo tolerance?

Theanine is well suited for benzo tolerance as it upregulates GABA(B)

Theanine blocks mGlu1, which is coupled with GABA-B. So by antagonizing and upregulating mGlu1, it upregulates GABA-B. The GABA-B upregulation happens after theanine wears off.

Also, it upregulates BDNF and GDNF.

GDNF (glial cell line-derived neurotrophic factor) supports the survival of dopaminergic and motorneurons

After some research I see that theanine is an AMPA antagonist, Kainate antagonist, a GABA-A agonist, and a Group One Metabotropic Glutamate Receptor antagonist. The Group One MGluR's boost the activity of NMDA receptors, so by blocking those receptors theanine is blocking NMDA.

This means theanine is a nootropic.

AMPA increases BDNF, and AMPA positive allosteric modulation is the mechanism of piracetam. This means theanine would upregulate AMPA, kainate, and Group One MGluR's. Once MGluR becomes upregulated NMDA would release more acetylcholine [you really want to keep NMDA below a certain level, even with upregulation, because beyond that there is 5HT1A downregulation and neurotoxicity]. AMPA would begin to act like it is under the influence of piracetam. There would be no subtle crash at the end of the AMPA upregulation.


Edited by sativa, 12 March 2016 - 08:06 PM.


#55 Mirage

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Posted 19 March 2016 - 04:54 PM

After experimenting with different dosages of DXM I can definitely say that it potentiates the side effects of all the stimulants I've been using along with it: Dexedrine, Ritalin and Modafinil. Especially the heart rate and hyperthermia. The tolerance is still developed, though not as fast, but still pretty fast.

 

I'm getting Memantine tomorrow. Will try it out and come back to you guys.

 

If anyone has a piece of advice on using DXM/Memantine to reduce tolerance to stimulants - I'd be grateful if you could share it with me.



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#56 Justchill

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Posted 29 June 2017 - 10:14 AM

Theanine does jack shit and it will not upregulate GABA receptors. It increases GABA in the brain.

 

I'm interested in upregulating my GABA receptors and I am wondering if strong NMDA antagonists can help with that and with anxiety.

Myself I don't take amphetamines and benzo's daily, maybe on a day Tomorrowland but not everyday. I do want to reset my GABA receptors. I quit a (low dose) etizolam habit cold turkey and I am recovering from it.

 

Memantine is impossible to source to Belgium, but 3-meo-pcp is. So what is your opinion about that one and how can you reset your receptors using it? Like 1-2mg every day for 2 weeks?

 

Other NMDA antagonists are lithium, magnesium, zinc, curcumin, uridine.. Lithium makes me calmer, I'm guessing that one helps too.






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