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Drugs/meds to lower glutamate

dopamimetic

dopamimetic

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Joined
Mar 21, 2013
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I know riluzole is said to be a glutamate reuptake enhancer and lower extrasynaptic levels of glutamate, and recently read that lamotrigine does similar by a different route but heard different things about it before. These two are the only drugs I know about that actually lower the output of glutamate instead of blocking its receptors (dissociatives for NMDA, topiramate for AMPA) or countering its activity (GABAergics).

Do we have some more agents?
 
dopamimetic said:
Do we have some more agents?
Click to expand...

Don't know, but I found this article saying that riluzole causes a 'rewarding' effect in animal tests while at the same time it prevents the conditioned place preference caused by morphine or amphetamine. This is said to be what happens with MK-801 and other NMDA antagonists, too.

www.sciencedirect.com

Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole

Previous studies have shown that antagonists at glutamatergic N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA…
www.sciencedirect.com www.sciencedirect.com

The side effects listed for riluzole look too bad for it to be used without an actual medical reason.
 
Actually what I read about riluzole sounds promising. The side effects listed on wikipedia don't sound that scary given that it is used in people with a terminal disease where it increases time required before artificial ventilation so I'd say we can ignore that one regarding decreased lung function. The list below doesn't exactly sound appealing but some mood stabilizers or antipsychotics seem worse to me.

Click to expand...

It shows promise in treatment of some mental disorders like anxiety and a sublingual formula is actually in clinical trials for it. The reason why I didn't try it yet is scarcity and astronomical prices - I read one single report on longecity where the user found it too speedy.

But was my idea too, that things lowering glutamate output might have similar effects to NMDA antagonists but maybe a different tolerance pattern and toxicology. There are some odds though like AMPA receptors.

What side effects did you read about?
 
I read that NAC (N-acetyl cysteine ) can help to modulate glutamate in the brain. It also has a number of great benefits. Worth checking it out
 
i react real real bad to anything glutamate related. NAC puts me into the most dissociative shitty state a person can imagine. Memantine almost killed me. Caffeine puts me into seizure state 101. I am surprised I still abuse alcohol though lol thats the worst of them all, but somehow after few glasses it normalizes me. At first it kind of does what Memantine and NAC do. Put me into dissociative confusion. But after a while, it normalizes me. Thats main reason I have been scared going back to DXM. It will put me into dissociative coma!

so do you think any of those drugs that lower glutamate might be good for me?

i believe i read some herbs and/or their isolates can do that. have to find the list if i still have it. very good reminder as i should take this serious now days.
 
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How much memantine did you take @allone, and how much NAC? I love memantine in supratherapeutic dosages but didn't feel anything at all from NAC and I did at least 1 if not 1.5g.

Caffeine afaik is an adenosine antagonist, not a direct glutamate modulator.

Yeah, dissociation comes with confusion and memory inhibition but for me that's actually beneficiary as it stops me from chronic over-thinking. Anybody interested in these things should try a low dose of 2-fluoro / deschloroketamine (or MXE if you find some) imho, it's entirely different than dirty old DXM.
 
10mg, not high. but regularly i was taking it for a week and it has a very long half life. so it built in my system and then i started drinking alcohol and taking suboxone, and man did i fuck up my brain! something went off. hasnt been the same since. i wish i never fucked with meds and alcohol, but here i am. and NAC, about 1 gram. i didnt feel it either but after alcohol binges, next day, it made me feel super confused. i think most of you guys havent experienced those horrible confusions and dissociations is because you havent abused alcohol long enough. thats the problem with me. trying to quit now, but i get nasty ass withdrawals... sucks.

whats 2-fluoro / deschloroketamine ? first time i hear of this. is it possible to find it? is it even legal?
 
allone said:
just remembered to add tianeptine. definatelly does something to glutamate. check it out
Click to expand...
It's an opioid, they all lower glutamate but at the price of upregulating nmda receptors, causing a rebound. Just checked google, which found me this:

pubmed.ncbi.nlm.nih.gov

NMDA and AMPA receptors are involved in the antidepressant-like activity of tianeptine in the forced swim test in mice - PubMed

It is known that tianeptine exhibits antidepressant-like activity. Its influence on the glutamatergic system is also known, but the mechanisms involved in this activity remain to be established. The aim of this study was to investigate the involvement of the glutamate pathway in the...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

But that's true for most antidepressants, they all become more effective when used together with nmda antags because these alone are strong antidepressants, at least when you think of the forcing swim test as model depression - anything which inhibits memory will improve outcome, same for euphorisants, most dissos are both.

Do you have a source for the claim that tianeptine directly interacts with glutamate? Or based on which effects, and dose, did you come to the conclusion?
 
A bit of background: GABA is the main inhibitory, and glutamate the main excitatory, neurotransmitters in the nervous system. In fact, the main ones by a loooong shot. GABA relaxes muscles, reduces anxiety, promotes sleep, and so on. Glutamate works in the opposite manner.

Theory goes that epileptics have a GABA deficiency, or a GABA: glutamate ratio with way more glutamate than GABA. This causes seizures. Similarly, people with mania are said to have an excess of glutamate. So, many anti-epileptics double as mood-stabilizers , and vice-versa...

GABA is metabolized into glutamate.

Glutamate is a bit of a mystery because astrocytes participate so much in the metabolism, and we know little about glia, though there are 5-10 times more glia in the brain than neurons. That's partially why the problem of too much glutamate: GABA is handled by increasing GABA, not decreasing glutamate. But the effect would be mostly the same.

Depakote is in-fashion. Just a sec...useful in all kinds of seizures. It's used as an add-on in psychotic disorders. Looks like it stops action potentials from reaching the end of the neuron and releasing nt's into the synapse; it does this by stopping the electric signal as it makes its way down the axon via stopping influx of sodium cations. Just as I thought, it inhibits the three enzymes that metabolize GABA into glutamate.

As for GABA reuptake inhibition as a mechanism, well that's a bit strange, as only metabotorpic GABAergic neurons degrade GABA through the reuptake pump and until its back in the presynaptic cell. And it's GABAa receptor subunits, ionotropic receptors, that produce the effects that we classically identify as GABAergic (anxiolysis, muscle relaxation, soporific, and so forth). I don't know what histone deacetylase is, but apparently by inhibiting it, there is some transcriptional/neurotrophic activity; I don't know where in the brain that would be.

Seems like it functions as, I dare say, a steroid. It promotes less estrogen, for example.
 
gaba is not metabolized to glutamate AFAIK, it's the other way around... glutamate is decarboxylated to form GABA.


also "lowering glutamate" is very vague and generalized, compare "increasing serotonin". You'd have better luck coming up with a successful treatment if you say *why* you want to "lower glutamate" - it may be that the problem is not directly related to that at all.

recall also that glutamate is an amino acid that is involved in protien synthesis, so you need a certsin amount or else you will waste away
 
sekio said:
also "lowering glutamate" is very vague and generalized, compare "increasing serotonin". You'd have better luck coming up with a successful treatment if you say *why* you want to "lower glutamate" - it may be that the problem is not directly related to that at all.
Click to expand...

I'm looking for a way to re-create the benefits of low dose dissociatives while circumventing the probably pretty bad upregulation of NMDA receptors. Also hope to find something that is prescribable but guess I'm out of luck there. Sorry, I've posted about this before but couldn't find the threads anymore - and then I was specifically asking for NMDAr's thinking that the shift of NMDA to AMPA activity which dissociatives seem to do might be relevant, still unsure about this. Topiramate being an AMPA agonist made me horribly forgetful at very low dose. But then I read about lamotrigine having other mechanisms to inhibit glutamate release.

Was questioning it myself again over and over when in depressive state, then at some point I am desperate enough to break with the oh so healthy sobriety and take some disso again just to find myself, depending on substance between some mins and hours later, being the other self again, the one I like. It is like a switch between glass half empty and half full. Anxiety and tension on/off. Social abilities vs fatigue on/off. The effect remains, independent of tolerance and duration of use. No pharm besides memantine, with which the DA agonism is too strong and which is hard to get a script for, comes remotely close. Only when escalating doses of dissociatives, when seeing the euphoria as the sole reason for using instead of doing other stuff with the energy, then things go downhill. Lost far too much time now cycling between these states and questioning myself, also looking for continuous supply and dealing with law enforcement.. I need something better.

Unfortunately now even that dirty old DXM becomes regulated around here, and with the NL pushing a ban for research chemicals, I am afraid to be left without 'treatment' anytime soon.

What worries me is that I think to have increased anxiety and inner tension when sober. As I have seemingly permanent tolerance to dissociatives, I have to think of increased NMDA density and the implications thereof. A bunch of papers suggests how bad this is for the brain and body - at least it should protect me from psychosis but sometimes I'd prefer some psychosis over this constant tension. I'm not that hypochondric or nocebo-sensitive, what I don't see or feel doesn't worry me but I feel these things and they make me mad. I know there is probably no way to know if it's really NMDA overexcitation or not, so all I have is that every single agent which antagonizes NMDA brings relief to that exact set of symptoms. Had them before but maybe less pronounced, and apparently borderline personality (which I have) is mediated by NMDA too.

Lamotrigine's still out, maybe, and riluzole whch I can't afford. K is far too short acting and too physically toxic.

Have tried to talk about this with neurologists and psychiatrists, they threw me right out of their office or wanted to prescribe me antipsychotics, escitalopram (which added to the tension in past), or valerian. Those few who advertise with being up to date or even with things like d-cycloserine/ketamine for treatment resistant MDD are so overrun that they refuse new patients. So I'm left with myself.
 
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dopamimetic said:
It's an opioid, they all lower glutamate but at the price of upregulating nmda receptors, causing a rebound. Just checked google, which found me this:

pubmed.ncbi.nlm.nih.gov

NMDA and AMPA receptors are involved in the antidepressant-like activity of tianeptine in the forced swim test in mice - PubMed

It is known that tianeptine exhibits antidepressant-like activity. Its influence on the glutamatergic system is also known, but the mechanisms involved in this activity remain to be established. The aim of this study was to investigate the involvement of the glutamate pathway in the...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

But that's true for most antidepressants, they all become more effective when used together with nmda antags because these alone are strong antidepressants, at least when you think of the forcing swim test as model depression - anything which inhibits memory will improve outcome, same for euphorisants, most dissos are both.

Do you have a source for the claim that tianeptine directly interacts with glutamate? Or based on which effects, and dose, did you come to the conclusion?
Click to expand...


Im sensitive to anything having to do with glutamate so i believe it does, but there are studies on google suggesting it; https://pubmed.ncbi.nlm.nih.gov/12372016/
i mean there are lots of studies saying probably does, but im not sure if it can ever be proven 100%.

anyway, im just very upset the post office lost my tianeptine today. was supposed to be delivered already and it isnt claiming it was. it upsets me because, its always my way out of some drugs im dealing with at times.
if you are in europe, you can get it from pharmacies as Coaxil without prescription in the eastern countries i was in, but maybe even western europe? its not really regulated well at all in europe. also its the real deal not the crappy powders from china i have to order!
 
Hi, so let me preface as I am currently diagnosed ADHD-C but primarily inattentive. the current DSM-V isn’t updated and a few psychs have decided on their own that ADHD-C could be something that is not ADHD like and is most likely SCT + Co-Morbid OCD. TLDR, the reason I bring this up is because while looking to help my symptoms, before my diagnosis, I spent about 11 months on the ketogenic diet.



While losing weight was great, the cognitive “energy” and overall uptake of focus really was the best thing that came out of it. And ever since, I looked up why it works and came across about how the diet was tested with people with Alzheimer’s and Parkinson’s, https://www.naomiwhittel.com/the-ketogenic-diet-and-gaba-connection/?amp, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356942/, and it’s attributed to an increase or inability to synthesize glutamate. In comes the ketogenic diet, which according to studies, helps synthesize glutamate into glutamine into GABA via GAD (glutmatic acid decarboxylase), which is helped via vitamin B6, which mostly comes from foods highly recommended by the diet (eggs, red meats, chicken). In a short trial https://pubmed.ncbi.nlm.nih.gov/23933905/, metadoxine ER, Pyridoxal phosphate dependent enzymes also play a role in the biosynthesis of four important neurotransmitters: serotonin (5-HT), epinephrine, norepinephrine and GABA. Metadoxine is basically B6 extended release and was shown improvement in ADHD-PI symptoms but was discontinued after the phase 3 trial, after the placebo was shown to be as effective however the trial was mostly for ADHD, but not specifically ADHD-PI.





So while researching this, I came across nmda antagonist, mainly Memantine. There are other nmdar antagonist like magnesium but has a weaker affinity. Memantine, being a nmda antagonist, it helps block excess nmda’r and the release of excess glutamate. MT being a acetylcholinesterase inhibitor, it inhibits the breakdown of acetylcholine into choline and acetate. In ADHD, Parkinson’s, and Alzheimer’s disorders, there’s a excess of Ca+ influx that makes the neuron excitory (release glutamate more than usual ). Memantine being a non-competitive antag of NMDAr, can inhibit the influx without disturbing and preserves the function of the synapse.



However, inhibiting acetylcholine too much can cause choline toxicity. So it must be slowly released or have a controlled release so it can broken down easier and the residual choline and acetate can be properly stored (chlorine) to make acetylcholine and acetate be converted into ketones.



With keto and Memantine together, theoretically amount of glutamate left that was slowly let out, that is released, can be quickly synthesized into glutamine (enough b6 to synthesize glutamate via high b6 diet) and into gaba. Ketones are made from acetate, that’s converted via the liver. Ketones having a high affinity for nicotonic receptors and gaba receptors, act like a glue similar to nicotine for gaba and that’s where the focus and energy enhancement comes from keto.
 
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