271 replies to this topic

[Galantamine]

D-Serine is a coagonist at the NMDA receptor and is thought to bind to the glycine binding spot, albiet with higher potency. In concert with glutamate and in the absence of magnesium, D-Serine activates the NMDA receptor and promotes calcium entry. The end result is increased transcription/translation of various gene products. In the hippocampus, activating this system promotes long term potentiation (LTP) via BDNF & trkB upregulation.

The racetams allosterically activate this system and would synergize well with D-Serine. Specifically, Aniracetam (or the ampakines) would promote magnesium displacement via AMPA activation & cellular depolarization, and Piracetam would synergize more locally on the NMDA receptor itself.

The product: https://www.prototyp...?ProductCode=DS

Some interesting studies:

D-serine regulation: a possible therapeutic approach for central nervous diseases and chronic pain.
D-Serine, an endogenous modulator of NMDA receptors has been shown to play a vital role in many neuropsychiatric functions such as learning, memory, nociception and implicated in pathological conditions like schizophrenia and Alzheimer's disease. We propose possible therapeutic approaches for some CNS diseases and chronic pain, targeting the D-serine levels by manipulating its uptake, biosynthesis and metabolism.
http://www.ncbi.nlm....pubmed/19519506

D-Serine: a key to synaptic plasticity?
Two discoveries have put D-serine in the spotlight of neuroscience. First, D-serine was detected in brain tissue at high levels. Second, it was found to act on the N-methyl-D-aspartate receptor (NMDAR). This receptor is central to use-dependent synaptic plasticity, the cellular process which is widely believed to underlie learning. The ensuing quest for the mechanisms of D-serine synthesis, release and clearance, as well as for its physiological significance has provided a wealth of experimental evidence implicating D-serine in synaptic plasticity. However some key questions remain unanswered. Which cells release D-serine and upon what stimuli? Is D-serine supply dynamically regulated? What is the fate of released D-serine? Answering these questions appears to be an essential step in our understanding of how NMDARs trigger synaptic plasticity and learning. This review will highlight some recent advances and avenues of enquiry in dynamic D-serine signaling in the mammalian brain with emphasis on neurophysiology.
http://www.ncbi.nlm....pubmed/22266400

Effects of low-dose D-serine on recognition and working memory in mice.
CONCLUSIONS: Our results show that treatment with D -serine can improve performance in tasks related to recognition learning and working memory, suggesting that this agent can be useful for the treatment of disorders involving declines in these cognitive domains.
http://www.ncbi.nlm....pubmed/21556803

In depth explanation of hippocampal glutaminergic signaling: http://hightowerphar...s-volume-1.html

[gizmobrain]

This is interesting for those who suffer from NMDA hypoactivity, but not so great for those who suffer from overactivity.

Of course, it would seem important to mention that overdoing this (like most things) would probably be bad. Looking at it's mechanism of action, anything that increases glycine, glutamate, or acts to increase NMDA transmission (Glutamic Acid, -racetams, Noopept, and several others) would be synergistic, but used recklessly, could cause too much NMDAr activation which would lead to excitotoxicity and neuronal damage.

However, this is true about most things

[Psionic]

Acute d-serine treatment produces antidepressant-like effects in rodents.

Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of d-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that d-serine modulates behaviours related to depression. The behavioural effects of a single, acute d-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. d-serine significantly reduced immobility in the FST without affecting general motor function. Both d-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, d-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to d-serine treatment. These findings suggest that d-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether d-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine.

http://www.ncbi.nlm....pubmed/21906419


Ketamine enhances the expression of serine racemase and D-amino acid oxidase mRNAs in rat brain.

We have evaluated the effects of the acute administration of noncompetitive N-methyl-D-aspartate receptor antagonist, ketamine, on the expression of serine racemase and D-amino acid oxidase mRNAs in several brain areas of rats. The ketamine administration produced a dose-dependent and transient elevation in the levels of serine racemase and D-amino acid oxidase mRNAs in all the brain areas. These findings suggest that there is a relationship between the gene expression of the d-serine-related enzymes and the blockade of the N-methyl-D-aspartate receptors.

http://www.ncbi.nlm....pubmed/16716293


D-serine added to antipsychotics for the treatment of schizophrenia.

BACKGROUND: Hypofunction of N-methyl-D-aspartate (NMDA) subtype glutamate receptor has been implicated in the pathophysiology of schizophrenia. D-serine is a full agonist of the glycine site of NMDA receptor, an endogenous cotransmitter enriched in corticolimbic regions and distributed in parallel with NMDA receptor. Supplementation of D-serine may improve the symptoms of schizophrenia.
METHODS: Thirty-one Taiwanese schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-serine (30 mg/kg/day), which was added to their stable antipsychotic regimens. Of these, 28 completed the trial. Measures of clinical efficacy, side effects, and serum levels of amino acids and D-serine were determined every other week. Wisconsin Card Sorting Test (WCST) was performed at the beginning and end of the trial.
RESULTS: Patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in WCST. D-serine levels at week 4 and 6 significantly predicted the improvements. D-serine was well tolerated and no significant side effects were noted.
CONCLUSIONS: The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia. Given the effects of D-serine on positive symptoms, a trial of D-serine alone in schizophrenia should be considered.
http://www.ncbi.nlm..../pubmed/9836012


So if I am strong responder to ketamine atidepressant effect, it means that I suffer NMDA hypoactivity? Subjective observing after single dose has detected increased insight into things (better understanding and seeing logical patterns), much better piano skills plus learning and fundamentally improved short term memory, thinking more out of the box (maybe its all signs of depression removal or schozephrenia blocking qualities). Although antidepressant effect remains for several weeks, improved learning lasts only 1-3 days.. I wonder how comparable are effects of supplementing with D-Serine against Ketamine.

Edited by Vojtech Mejzlik, 08 July 2012 - 09:23 PM.

[NMDAstronaut]

I have been looking for this for a while. definitely going to try it. I've tried D cycloserine with varied success but had to buy it from overseas. The cyclo was no panacea unfortunately however

Edited by NMDAstronaut, 10 July 2012 - 06:38 AM.

[middpanther88]

I'd love to hear everybodys experience w combos w dserine!

[medievil]

I have been looking for this for a while. definitely going to try it. I've tried D cycloserine with varied success but had to buy it from overseas. The cyclo was no panacea unfortunately however

Stuff only is a partional agonist and therefor weak sauce.

Glycine, d serine are full agonists, sarcosine is a glycine reuptake inhibitor and a glycine agonist itself, they will all be stronger.

[Psionic]

I have been looking for this for a while. definitely going to try it. I've tried D cycloserine with varied success but had to buy it from overseas. The cyclo was no panacea unfortunately however

Stuff only is a partional agonist and therefor weak sauce.

Glycine, d serine are full agonists, sarcosine is a glycine reuptake inhibitor and a glycine agonist itself, they will all be stronger.

Medievil, so what you think if you can choose one, which one of these can be most effective for schizophrenia cognitive decline (if ketamine or mxe works great in this case but causes memory impairment)?

Edited by Vojtech Mejzlik, 10 July 2012 - 04:48 PM.

[gizmobrain]

So, I've responded well in the past to Adderall for my lack of motivation, but it has wicked fast tolerance in this area. I have had a lot of theories on why that is the case, but I'm beginning to wonder if my ADD/lack of motivation is actually related to hypo-NMDA activity. According to this study, glutamate and d-serine are released in higher quantities when mice are given amphetamines.

I'd like to get my hands on some to test this theory, but I can't afford to cough up $50 right now. Anyone find any cheaper sources?

Edited by zrbarnes, 10 July 2012 - 06:19 PM.

[medievil]

I have been looking for this for a while. definitely going to try it. I've tried D cycloserine with varied success but had to buy it from overseas. The cyclo was no panacea unfortunately however

Stuff only is a partional agonist and therefor weak sauce.

Glycine, d serine are full agonists, sarcosine is a glycine reuptake inhibitor and a glycine agonist itself, they will all be stronger.

Medievil, so what you think if you can choose one, which one of these can be most effective for schizophrenia cognitive decline (if ketamine or mxe works great in this case but causes memory impairment)?

Sarcosine and d serine are generally the most effective but sarcosine only works for negative symptions d serine treats both positives and negatives.

It also depends what negatives you want to tread, i think that name is way to broad there atleast should be a differentation btw the pure cognitive negatives and the more emotional ones (depression, ocd, ADHD, anhedonia) and id say even that is too broad as the treatments for OCD and anhedonia for example will be quite differend.

@Zrbarnes
Hypoglutaminergic activity indeed plays a huge role, ADHD is quite simular to shizophrenia (like AVPD) they are more like mini versions of shizophrenia with only a negative symption and all are treatable with amphetamine.

Methylphenidate is as effective as amphetamine for ADHD if im correct while that doesnt release any glutamate.

[medievil]

I suspect that d serine would be higly synergetic with pregnenolone as that upregulates nmda and keeps nmda agonized, d serine would potentiate this as it keeps the nmda site open trough the glycine receptors.
Also clozapine releases both togheter with glutamate wich makes it very glutaminergic for those interested in this for shizophrenia, that ap is very effective for negatives so for those trying to replicate it thats good info.

[gizmobrain]

@Zrbarnes
Hypoglutaminergic activity indeed plays a huge role, ADHD is quite simular to shizophrenia (like AVPD) they are more like mini versions of shizophrenia with only a negative symption and all are treatable with amphetamine.

Methylphenidate is as effective as amphetamine for ADHD if im correct while that doesnt release any glutamate.

Interestingly enough... Methylphenidate does nothing for me but induce nausea and overall weirdness, while amphetamine does wonders for my motivation (but causes all kinds of nasty side effects typically linked to too much dopamine).

It's mostly because of your posts comparing ADHD with schizophrenia that I started to research schizophrenia treatments for anhedonia. It's very interesting, because there are a lot of symptoms that overlap between mine, yet there are some very big ones that do not.

Maybe this is a bit too simplistic, but I think schizophrenia might be a couple conditions on top of each other, and I have one but not the other.

I've not really directly targeted the NMDA and glutamate/glycine/d-serine system before now, only accidentally by use of Adderall and Forskolin. I also suspect Noopept to affect this system too, though I haven't figured out how to control it's effects yet.

Edited by zrbarnes, 10 July 2012 - 08:23 PM.

[medievil]

Its not like that, its more likely that someone with multiple conditions relates to something big that overlaps them (such as someone with adhd, ocd, anhedonia, depression would kinda relate to shizophrenia (many never get more then just negs and dont develop shizo) rather then someone having differend disorders togheter.

The reason for that is that its more likely someone has a universal cause for all disorders rather then have differend disorders that dont have the same rootcause. Shizophrenia is caused by glut hypoactivity wich makes it one disorder and not a bunch differend ones togheter.

[gizmobrain]

I just realized that the company that is selling D-serine is 45 minutes away and that I used to know a couple of people that worked at its parent company. It's a small world....

Too bad they don't work there anymore. I'm not really in the place to drop $50 on it. Maybe I'll save my pennies.

[X_Danny_X]

I have problems staying still and concentrating when learning things i hate. in fact even with some fun things, i get the urge to just move around or i go off into my little own world.

i really want this guy to work in improving intelligence. i wonder how this will work with the CILEPT stack.

[gizmobrain]

As I brought up in the CILTEP thread, Forskolin increases the probability of glutamate release. Glycine and glutamate binding sites are both involved in activating the NMDA receptor. If lack of glycine is currently a limiting factor in one's "CILTEP enhanced" brain, then D-serine would seem to be a strong synergy, since D-serine has even a stronger affinity for the glycine site than glycine itself.

However, for those that suffer from too much NMDA activity, supplementing with D-Serine would likely increase their problems.

[X_Danny_X]

How can you tell if you have a lack of glycine?

[gizmobrain]

I think at this point, experimentation with a close eye on health and safety is the easiest way to tell. Glycine has been studied to treat depression, schizophrenia, and a host of CNS disorders. It's not very common in America for doctors to pursue this though, because it is generally believed that glycine deficiency is uncommon. I have not really studied this in great deal yet (though it is currently parallel to my main focus), so I'm sort of out of my element.

In the past, I have trialed Trimethylglycine (TMG) supplementation, but never in combination with CILTEP.

Edited by zrbarnes, 13 July 2012 - 06:59 AM.

[X_Danny_X]

So activating the NMDA receptor, helps increase memory and intelligence? I have been studying in inhibiting COMT since COMT can cause problems in executive function but seems that activating more so the NMDA receptor is what I need with the CILTEP stack in terms of increasing intelligence since CILTEP is mainly for long term memory.

[gizmobrain]

The studies posted above seem to implicate NMDA activation as a pathway to increasing recognition learning and working memory.

However, it is just as important to keep it balanced, because over-activation of NMDA receptors lead to neuronal death. This is what I've been discussing so far (by myself, ) in my D-serine + Pregnenolone for NMDAr activation? thread.

Edited by zrbarnes, 13 July 2012 - 07:05 AM.

[X_Danny_X]

Well I have problems staying still, sometimes I have to move around when I am studying after a while. Also generally when I have to move around is when I see something I like and I envision myself doing that and I walk back/forth while thinking about it.

Strange, I was always wonder why I have that urge and battling myself if its ADD or ADHD. Could be too much activation of NMDA receptor. I guess I will speak with my doctor about it but at the sametime they have no clue about nootropics and give me some outdated advise and information.

I guess I have to conduct my own research.

[gbpackers]

any word from the people that were testing this stuff out? I've been thinking about buying it to use with piracetam but not sure if I want to shell out 60 bucks for something that doesn't really do anything

Edited by gbpackers, 20 July 2012 - 05:52 AM.

[golden1]

Is there anything close to the opposite of these(I am seeking to lower NMDA activation) which is something simple like glycine or d-serine? I feel like it would realllly make tapering off benzodiazepines less annoying if I could easily lower NMDA activation...anyone? I know huperzine A has NMDA antagonism which excited me, but then I realized that the common isomer found in the plant and sold everywhere is ~35x more effective as an ach breakdown inhibitor.. making the dose needed for noticeable effects on NMDA antagonism impossible without overdosing on acetycholine... sigh. Maybe I can find the other isomer for sale somewhere.. if i remember correctly the plant only contained the less active isomer; Anyway I like the effect of 100mcg huperzine A even with it just acting to increase acetylcholine, it feels much much cleaner and natural than galantamine to me.

But yeah kind of off topic but I thought I'd ask.


edit: Hmmmm.... http://en.wikipedia....al_significance Just happen to have some, wonder if it will help, have a semi-good feeling about it, but it can't be that good if its just a super common amino acid.. plus I eat a lot of the foods high in it.. but maybe I will see what higher doses do on an empty stomach..

Edited by golden1, 20 July 2012 - 06:28 AM.

[gizmobrain]

I use Magnesium L-Threonate for the purpose of NMDA antagonism.

Also N-acetylcysteine also can help regulate NMDA activity..

[SuperjackDid_]

Anything else should avoid on NMDA hypo-activity ?,i react very badly on Piracetam ,ALA help me a lot but i can't take anything that stimulate brain further ,except anything can calm down .
Or just my brain damaged? but why i can't take anything at all ,Caffeine make me sleepy instead of mental clarity and more energy like before taking Piracetam

I have stop Piracetam more than month except sometime low dose while on exercise for better ball handing and more creative play ,or should i avoid PI completely ? Sorry for little off topic but
Piracetam might really involve in this symptom that occured to me .

I might try D-Serine ,but i almost tried anything and i have my conclusion not to try anything more until it effective proofed .

NMDA receptor antagonist give me more depression ,except Huperzine A give me better mood that i continue taking it .
N-acetylcysteine give me irritability and tingling symptom like it stimulate brain more further and give me that effect ,this one not calming supplement but it give good motivation and concentration

[gizmobrain]

Just to let everyone know: I noticed that the title of this thread is labelled as "new", yet there have been other products containing D-serine before now. Even typing in "D-serine" into the search on this site will bring up some threads from a couple years ago.

I have the bottle sitting in front of me. $40 was a lot to cough up on a gamble, but I thought I'd give it a shot (If it works for my purposes, it will help me get off my butt and make far more than $40 in return, right?).

So far, I will admit, I haven't been very scientific about controlling the variables. I got over-eager and tried small doses of a bunch of stuff all at once, the first day I got it. Objectively, I can tell you this: the powder is white, crystalline, dissolves readily in water, and tastes like sugar (the packaging is pretty good, too, which subjectively increases product confidence).

Subjective effects are definitely subtle (I don't feel under the influence), and I definitely have not put in the proper variable controls yet to be able to positively attribute the effects to the D-serine alone. But I can tell you this: at the standard 1.5g dosage, there doesn't seem to feel an immediate effect.

I say all this to say the following: Usually, I'm quite complacent with my status in life. However, I have wanted to quit my unfulfilling, dead-end job this week more than ever. I have been looking for jobs related to my field of interest, and have pro-actively been trying to improve my current situation. So, even though I haven't been much more motivated in the micro-aspects of my life, I have been more motivated on the macro scale.

I will try to report back later to see if this can be attributed to the D-serine, and if any other effects become apparent.

Edited by zrbarnes, 20 July 2012 - 09:19 AM.

[Psionic]

thanks zrbarnes, please let us updated. I really wonder how its effects can be compared to short term memory boost of NMDA antagonism induced by ketamine or MXE.. But you should have something where you can compare its effects. I easily do that on note sheet reading and remembering on piano or by playing dual n back (althought i didnt noticed improvement in wm) where I am able to vividly remeber positions.. I think increased LTP plays its role here and the difference of learning one song within one day on its influence versus regular learning for about a week is striking.

[gbpackers]

Just to let everyone know: I noticed that the title of this thread is labelled as "new", yet there have been other products containing D-serine before now. Even typing in "D-serine" into the search on this site will bring up some threads from a couple years ago.

I have the bottle sitting in front of me. $40 was a lot to cough up on a gamble, but I thought I'd give it a shot (If it works for my purposes, it will help me get off my butt and make far more than $40 in return, right?).

So far, I will admit, I haven't been very scientific about controlling the variables. I got over-eager and tried small doses of a bunch of stuff all at once, the first day I got it. Objectively, I can tell you this: the powder is white, crystalline, dissolves readily in water, and tastes like sugar (the packaging is pretty good, too, which subjectively increases product confidence).

Subjective effects are definitely subtle (I don't feel under the influence), and I definitely have not put in the proper variable controls yet to be able to positively attribute the effects to the D-serine alone. But I can tell you this: at the standard 1.5g dosage, there doesn't seem to feel an immediate effect.

I say all this to say the following: Usually, I'm quite complacent with my status in life. However, I have wanted to quit my unfulfilling, dead-end job this week more than ever. I have been looking for jobs related to my field of interest, and have pro-actively been trying to improve my current situation. So, even though I haven't been much more motivated in the micro-aspects of my life, I have been more motivated on the macro scale.

I will try to report back later to see if this can be attributed to the D-serine, and if any other effects become apparent.

I was under the impression that you don't really notice anything from D-Serine, but that it will amplify the effects of piracetam and ampakines. The main reason I was looking forward to trying it was to see what effect it has on my piracetam regimen.

[gbpackers]

bump any reviews on this?

[abelard lindsay]

I say all this to say the following: Usually, I'm quite complacent with my status in life. However, I have wanted to quit my unfulfilling, dead-end job this week more than ever. I have been looking for jobs related to my field of interest, and have pro-actively been trying to improve my current situation. So, even though I haven't been much more motivated in the micro-aspects of my life, I have been more motivated on the macro scale.

Wow, sounds exciting! Any updates on the effects?

[abelard lindsay]

I tried some of this. It made me a little more OCD than usual. It may have had some mild positive effect on my short term memory. I tied my high score on cambridgebrainsciences.com challenge (52). What kinds of tests are you guys using to measure working memory? I guess I should try a before and after stroop test.

Edited by abelard lindsay, 03 August 2012 - 11:05 AM.