271 replies to this topic

[ScienceGuy]

You are still very incorrect, and I would ask you to please take this to another thread. Not only is lyme disease highly treatable, but it is self-resolving even without antibiotics for the greater majority of patients (demonstrated an enormous study by Yale University). Neuroborreliosis is exceptionally uncommon and is not related to BBB dysfunction.

Indeed lyme disease is often transmitted with other rickettsia, although they too are highly treatable, self-resolving for most, and have nothing to do with the BBB (they are RBC membranotrophic).

Suffice to say, your point is invalid and the evidence you have used is wrong, disorganized, out of context, and mildly humorous. I'm guessing, pre-med?

With the utmost respect, NO, I am NOT incorrect; it is YOU that is wholly incorrect with regards to your both sublimely arrogant and ignorant opinion of how to properly diagnose and treat TICK-BORNE PATHOGENIC DISEASES, including LYME DISEASE; and I won't "take this to another thread" since I am responsibly advising individuals against self-administering NMDA RECEPTOR AGONISTS, including D-SERINE wherein there is a pre-existing medical condition that is causing NMDA RECEPTOR OVERSTIMULATION; as opposed to your wholly irresponsibly trivialising TICK-BORNE PATHOGENIC DISEASE.

The fact of the matter is that the subject of LYME DISEASE and the reoccurrence and persistence of symptomatology in the vast majority of patients in spite of the 'text book' diagnosis and treatment guidelines is very controversial. Let us agree on that point at the very least shall we?

You claim to be a doctor, wherein you have supposedly committed your life to improving the lives of others through properly diagnosing and treating disease. Well, I strongly urge (which given your apparently incurable God complex will almost certainly be ignored) that you devote some considerable time to reading through the many Internet Forums devoted to LYME DISEASE and populated by many, many individuals who according to you are "incorrect" in claiming that they are and have been suffering chronic, often incapacitating illness due to LYME DISEASE for years, in spite of medical treatment with the 'text book' PER ORAL administration of DOXYCYCLINE for the specified 3 WEEKS (which is what YOU would prescribe for treating diagnosed LYME DISEASE, isn't it?).

I am not going to waste my time getting into the whole LYME DISEASE debate with you, as I can already tell from your attitude (which by the way, in my humble opinion, stinks and is a perfect example of why this particular area of medicine is equivocal to being in the Dark Ages when it comes to proper diagnosis and treatment).

I do not in fact feel the need to prove you without a doubt to be incorrrect in your perspective relating to LYME DISEASE, since your opinion is already proven to be a fallacy by the MILLIONS of individuals who have been completely failed by the existing medical establishment and left to suffer for years without proper diagnosis and treatment of their TICK-BORNE PATHOGENIC DISEASE related chronic illness. You can choose to stick your head in the sand and repeat "I don't believe in LYME DISEASE" and "lyme disease is highly treatable" like a parrot with your eyes and ears closed until the cows come home; however, there are quite literally MILLIONS of people suffering horrendously right now from chronic illness caused by TICK-BORNE PATHOGENIC DISEASE who would most strongly disagree with you.

(N.B. Please kindly note that whenever I refer to "LYME DISEASE" I in fact refer to ALL pathogenic diseases contracted concomitantly, wherein proper diagnosis is part of the problem)

If you are at all open minded you should go check out the medical research by one DR JAMES SCHALLER, who is one of the very few physicians to fully understand how to properly diagnose and treat TICK-BORNE PATHOGENIC DISEASE. For your enlightenment I have attached two excerpts of his published texts titled "WHY LYME TREATMENTS FAIL" (parts 1 and 2). I strongly urge that you read them and also read his many published medical papers and text books on the subject of how to properly diagnose and effectively treat TICK-BORNE PATHOGENIC DISEASE. Personally, I know your sort and I believe that your ego will prevent you being man enough to do so; however, who knows? You might surprise me!

Incidentally, I myself happen to be a recovering LYME DISEASE sufferer; wherein I lost several years of my life to chronic, incapacitating illness causes by TICK-BORNE PATHOGENIC DISEASE, before, due to my own sheer determination, I was finally diagnosed as suffering from concommitent chronic infections of BORRELIOSIS, BABESIOSIS and BARTONELLOSIS; and for what its worth (though this will likely fall on deaf ears) all three infections were practically unaffected by the 'text book' recommended treatment for LYME DISEASE; however, thanks to proper diagnosis and treatment I am now practically cured. So I have first hand experience regarding this matter and hence there is nothing that you can say that will chance my opinion on the subject. You telling me that I am "incorrect" that I suffered chronic incapacitating illness for all those years, and that I am "incorrect" that the 'text book' recommended treatment for LYME DISEASE failed to cure the patient (me), despite the fact I have the medical test results that irrefutably prove it to be so... I could go on...

The sooner physicians like you wake up, the sooner you will stop being part of the problem with regards to precisely why so many individuals are unecessarily left to suffer chronic illness as a direct consequence of improper diagnosis and treatment of TICK-BORNE PATHOGENIC DISEASE

I fully realise that your enormous EGO will likely cause you to attack me in response to my straight talking, but suffice to say that I am not going to argue with you on this subject any further. In my humble opinion, with regards to your perspective on LYME DISEASE you are wrong; plain and simple. Anyone with half a brain can within seconds find evidence via the Internet of the many, many individuals who suffer chronic illness due to LYME DISEASE for years as a consequence of improper diagnosis and treatment; I will choose to let their MILLIONS of pre-existing postings via the numerious respective Lyme Forums prove your ignorance.

I will just leave you with this thought... by maintaining your existing perspective on LYME DISEASE you are effectively turning your back on the many individuals whose lives are destroyed by it, and in doing so you make yourself part of the problem, as opposed to the solution

Either way, I am sure that you cannot disagree with the fact that individuals with a pre-existing medical conditioned wherein NMDA RECEPTOR OVERSTIMULATION occurs should avoid self-adminstering NMDA AGONISTS, including D-SERINE.

Regarding to NMDA overstimulation I wonder hows the effects of NMDA antagonists (alcohol, dissociatives) comparable to NMDA agonists mentioned here? Since I discovered their effects to be somewhat (but impairs some other processes/its related more to decisions making) memory-boosting and causing clear thoughts to arise (I got borreliosis some years ago), so can it be a sign that I have NMDA already overstimulated? Hows then effects of NMDA agonists to person with already overstimulated NMDA (worse short term memory/cognitive impairment)?

Oh for the love of god. I'm done with this forum.

You need to work on your PR SKILLS, since your arrogant attitude is not going to make you many friends... Not everyone on this forum is the all-knowing oracle of all things medicine related that you seemingly believe yourself to be... (and please do not kindly take that as an invitation to attack me again)

Your comment in reply to Psionic's post is a perfect example of how your attitude stinks... you do realise you just insulted him, right?

Attached Files

•  WHY LYME TREATMENTS FAIL - PART 1.pdf   219.02KB   4 downloads
•  WHY LYME TREATMENTS FAIL - PART 2.pdf   182.2KB   2 downloads

Edited by ScienceGuy, 27 August 2012 - 05:35 AM.

[CIMN]

i don't like when people on the forum needlessly insult each other, we need teamwork. love to hear everyones opinion and knowledge.

Edited by CIMN, 27 August 2012 - 05:57 AM.

[Galantamine]

Your comment in reply to Psionic's post is a perfect example of how your attitude stinks... you do realise you just insulted him, right?

I'm not going to argue with an individual with an elementary level of knowledge, and hysterically long diatribes to match. Based on your posts in this thread, I'm quite certain that your "recovering" lyme disease was a manifestation of a hypochondriasis. If you want an actual Evidence Based Medicine approach, refer to the articles I posted previously, and not some random internet physician.

Nevertheless, D-Serine doesn't predispose to excitotoxicity even in the presence of some imagininary illness (even if it were real), because of the dynamics of the compound with its receptor. D-Serine is a co-agonist, and requires numerous criteria to be met prior to agonism. In humans and higher mammals, it requires preceeding agonism of the AMPA receptor, membrane depolarization, NMDA magnesium displacement, and accompanying binding with glutmate (or DAA/NMDA). It gets more complicated from here (receptor autoregulation, increased membrane electrical potential) but I won't confuse you. Thus, even supraphysiological levels of D-Serine will not activate the receptor. In mice, glutaminergic receptor dynamics are different (and you would know that if you had any actual scientific education). Taking DAA with D-serine still does not predispose to excitotoxicity because DAA has no affinity for the AMPA receptor.

[unbeatableking]

ScienceGuy, please go.

I'd rather have a gruff, tactless yet extremely knowledgeable person like Irish MD on here than a 'nice' simpleton.

If you want to make friends then go elsewhere. Irish is actually contributing information that the rest of us can use.

Christ. I don't get why people are so sensitive about being corrected using information that is both sound from a logical perspective and science-based. This is a science forum. People should stop being so sensitive.

And having an 'opinion' does not make you immune to criticism. We are putting chemicals into our bodies for pete's sakes, I do not care neither do I think anyone should listen to a layman on the topic just because he is entitled to an opinion, not unless he has the science to back it up.

If you want to do that than FINE. It's your body.

BTW. Irish MD is a doctor with a biochemistry degree.

Edited by unbeatableking, 27 August 2012 - 03:58 PM.

[unbeatableking]

I hope I don't witness the forced removal of an extremely knowledgeable member just because he is unwilling to 'hold your hand' and 'give you a pat on the back'.

Yeah. I'd expect as much from this forum. I mean this is the same forum that fell for Hyperspace's BS.

[Psionic]

IrishMD: I am sorry if my post sounded somewhat stupid, I just wanted to ask hows the nootropic effect of NMDA antagonism and agonism comparable. It seems more complicated than I thought at first. Please note that nootropic effect of NMDA antagonism is only my subjective and can be caused by many co-factors.

I am also for more knowledgeable persons to be here and be able to explain whats behind the curtain and not to turn discussion only to 'subjective' experiences which vary from person to person. Thanks.

[unbeatableking]

^

Your question isn't very clear.

The agonism of NMDA receptors from a nootropic perspective hinges on the capacity to increase the influx of Ca 2+ ions into the axonal membrane, leading to excitatory activity. Consequently, too much of this can lead to oxidative damage and ultimately, the apoptosis of neural cells. This is what we are trying to avoid, although Irish MD has shown that such an effect is highly improbable when speaking in terms of D-serine.

NMDA antagonism has no perceptible nootropic effect. In truth, the literature goes that the antagonism of NMDA receptors is counterproductive from a cognition perspective.

And when I say 'counterproductive' I mean going below baseline levels. Returning glutaminergic activity to homeostatic levels is another issue entirely.

And no, they are in no way comparable. Ketamine, a bodybuilding staple during the 70's and 80's, is an NMDA antagonist with an inhibitory effect on the CNS, ergo, it is a potent sedative.

NMDA agonism would present itself in an entirely different fashion, with the most common physical manifestation being seizures (indicative of excess excitatory CNS activity). Which is why ketamine is used as an adjunct in treating seizures.

Edited by unbeatableking, 27 August 2012 - 04:44 PM.

[ScienceGuy]

ScienceGuy, please go.

I am sorry if I went overboard about the whole LYME DISEASE matter, but IRISH MD's attitude and blinkered narrow-minded ignorance regarding TICK BORNE PATHOGENIC DISEASE seriously struck a nerve in me, given the 15 years' of hell, extreme pain and suffering I endured as a direct consequence of physicians precisely like IRISH MD failing to properly diagnose my illness. God help anyone who is infected with TICK BORNE PATHOGENIC DISEASE who has IRISH MD as their doctor!

BTW. Irish MD is a doctor with a biochemistry degree.

IRISH MD is a doctor with a biochemistry degree... who has astonishingly demonstrated that he is wholly ignorant with regards to the proper diagnosis and treatment of TICK BORNE PATHOGENIC DISEASE, including its effects on the BBB and NMDA RECEPTOR... and furthermore has stated that in his professional opinion I am a HYPOCHONDRIAC, which is extraordinarily irresponsible and as it happens easily disprovable given the facts that my illness was diagnosed by the UK's foremost specialist in TICK BORNE PATHOGENIC DISEASE; and corroborated by one of the world's leading researchers in said area of medicine, who has published no less than 29 medical books and 27 medical research papers (incidentally that's the "Random Internet Physician" he insulted by the way); and irrefutably confirmed by no less than 12 laboratory test results... If IRISH MD was my doctor I would be dead. Period. And that's the guy whose advice you'd prefer to follow... like a lamb to the slaughter... Well good luck with that! It's clear my time spent on this thread is a waste and hence is better invested elsewhere...

For what it's worth I welcome IRISH MD and I hope that the fact he and I have butted heads over the whole controversial subject of LYME DISEASE won't demotivate him from contributing his valuable expertise to this forum.

Anyway, I am respecting your wish and 'going'... toodaloo

Edited by ScienceGuy, 27 August 2012 - 05:32 PM.

[Galantamine]

IRISH MD is a doctor with a biochemistry degree... who has astonishingly demonstrated that he is wholly ignorant with regards to the proper diagnosis and treatment of TICK BORNE PATHOGENIC DISEASE,

I generally let my content speak in place of my accomplishments, but this statement could not be more wrong. I have spent time in Lyme, CT, and have participated in research through Yale university in the area of Lyme disease and its effects on cardiac conductivity. You are free to participate in this thread, but I would advise you to limit your hysteria-provoking/ill-conceived hyperbole to that which is relevant and science-based.

[CIMN]

i think this thread is getting a bit over dramatic, its main focus is on D-serine. I understand that you are very passionate ScienceGuy about lymes disease glutamate receptors in relation to that but this thread will get off track of main discussion. Kindly saying this, as i don't think a person has to be cruel when making a point. But, please make a thread, outside of this one for discussion. Indeed you brought up good points in regards to predisposed issues when taking a substance. I'm sure you mean well.

[unbeatableking]

With that being said...

Would D-Serine possess the same cortisol inhibiting properties as Phosphatidylserine? I know this effect is one of the reasons why the said phospholipid is so favored amongst nootropic circles, but can the same be said for D-Serine?

BTW, save for research ethics and what-not? Science has no basis in 'kindness' or 'affection'. Science just IS.

Anyone who has written a basic experimental paper would know this. Anyone who has ever gone to a conference or attended a lecture would know this as well.

You don't get a pat on the back for 'trying'.

I agree that there is no need for ad hominem insults and what-not, but I don't recall Irish MD saying anything of that sort to ScienceGuy. The comprehensive edit ScienceGuy did on his first post in this topic should tell you something.

Edited by unbeatableking, 27 August 2012 - 05:50 PM.

[ScienceGuy]

I generally let my content speak in place of my accomplishments, but this statement could not be more wrong. I have spent time in Lyme, CT, and have participated in research through Yale university in the area of Lyme disease and its effects on cardiac conductivity.

Let's agree to disagree and shake hands as friends, OK?

Another time and another place, if you are interested, I would gladly continue our academic discussion relating whether or not chronic illness is caused by TICK BORNE PATHOGENIC INFECTION(S) and their proper diagnosis and treatment, wherein you astonishingly seem to be of the view that it isn't; but I know and am able to prove irrefutably that it is; but not here and now as I don't want to derail this thread any more than I already have.

You are free to participate in this thread, but I would advise you to limit your hysteria-provoking/ill-conceived hyperbole to that which is relevant and science-based.

With regards to "hysteria-provoking/ill-conceived hyperbole"; let's agree to disagree on that also, OK? My original posting was indeed "science-based" given it included scientific substantiation to support my statement regards CNS LYME DISEASE inducing NMDA RECEPTOR OVERSTIMULATION through elevation of QUINOLINIC ACID, a known NMDA RECEPTOR AGONIST, which in cases of CNS LYME, as stated in the published study, is most certainly present in the CSF and BRAIN.

For what it's worth I would like to apologise for derailing your thread by my overreacting to your seemingly dismissing / trivialising the horrors of TICK BORNE DISEASE(S). Given my personal medical history, including many years of extreme suffering the likes you could not even begin to imagine, you struck a raw nerve. Again, my humblest apologies.

Edited by ScienceGuy, 29 August 2012 - 05:00 PM.

[ScienceGuy]

The comprehensive edit ScienceGuy did on his first post in this topic should tell you something.

Adding a single sentence to clarify the intended meaning of my post (which I wrote in a hurry at 5am UK time) and adding 3 words to one of the existing sentences for the same reason can hardly be described as "comprehensive edit". **ROLLS EYES**

Are you and IRISH MD dating or something?

OK, I'm not going to respond to any more of this BS, so sorry to everyone for my derailing the thread... back to the topic!

Edited by ScienceGuy, 27 August 2012 - 06:17 PM.

[unbeatableking]

^

No. I am simply aware of Irish MD's credentials in addition to his contributions. He's legit. Authentic, so to speak.

Nothing about him reeks of 'fraud'.

Hmm. On the other hand!

Were you and Hyperspace21 dating?

Edited by unbeatableking, 27 August 2012 - 06:24 PM.

[ScienceGuy]

^

No. I am simply aware of Irish MD's credentials in addition to his contributions. He's legit. Authentic, so to speak.

Nothing about him reeks of 'fraud'.

Hmm. On the other hand!

Were you and Hyperspace21 dating?

Perhaps you didn't read this:

OK, I'm not going to respond to any more of this BS, so sorry to everyone for my derailing the thread... back to the topic!

Edited by ScienceGuy, 27 August 2012 - 06:39 PM.

[Psionic]

Your question isn't very clear.

NMDA antagonism has no perceptible nootropic effect. In truth, the literature goes that the antagonism of NMDA receptors is counterproductive from a cognition perspective.

I really didnt know how it was possible but after a single dose of MXE I was able to learn dozens of things at rapidly increased rate (approximately up to 36 hours after dosing), I can surely claim that my short term memory was increased (I have tested numerous times on Spatial working memory updating http://cognitivefun.net/test/23) So I wonder how it can be explainable. There was also thread about its anti-depressant properties (http://www.socialanx...ressant-114431/) so it leads me to conclusion that my cognitive impairment is caused mainly by depression and when removed at least for short amount of time I am able to function at normal rate..

So if this statements are true I may know whats really going on:

"ketamine exerts its anti-depressant effect by
blocking NMDA glutamate receptors (stronger than memantine)
inhibiting GABA interneurons
disinhibition of AMPA recepters
induction of mTOR
and finnaly synaptogenesis

all of which takes place in the prefrontal cortex."

So the only thing I previously thought was that D-Serine could potentially increase learning rate close to what MXE did to my conditions but it seems much more complex now..

[gizmobrain]

Chronic exposure to partial NMDA antagonists is thought to increase short term memory by the NMDA receptor up-regulation that takes place as a result.

' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/8601798']
NMDA receptor upregulation: molecular studies in cultured mouse cortical neurons after chronic antagonist exposure.

Source
Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764, USA.

Abstract
We examined the possibility of changes in gene expression of the NMDA receptor subunits after chronic antagonist treatment. Exposure of neurons to the NMDA antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP-5) produced an increase in the levels of the R2B mRNA subunit. Concomitant exposure of neurons to AP-5 and NMDA reversed the upregulation. Chronic AP-5 treatment increased the R1 polypeptide, whereas no change was observed in the levels of mRNA encoding the R1 subunit. A more pronounced increase was observed in the R2A/B polypeptides. These data demonstrate that chronic treatment with NMDA antagonists selectively upregulates the NMDA receptor mRNAs and polypeptides. Furthermore, antagonist treatment produced a differential regulation of the R1, R2A, and R2B subunits in cortical neurons.

PMID: 8601798

→ source (external link)

This is the proposed reason that Magnesium L-Threonate increases short term memory.

' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/20152124']
Enhancement of learning and memory by elevating brain magnesium.

Source
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract
Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.

PMID: 20152124

→ source (external link)

My gut says that NMDA agonist during the day, and safe NMDA antagonists during the night is the way to reap benefits from both. However, I don't know if a 12 hour period of NMDA antagonism is enough to cause upregulation.

Anyone have any information on this?

Edited by zrbarnes, 27 August 2012 - 10:20 PM.

[Galantamine]

I generally let my content speak in place of my accomplishments, but this statement could not be more wrong. I have spent time in Lyme, CT, and have participated in research through Yale university in the area of Lyme disease and its effects on cardiac conductivity.

Let's agree to disagree and shake hands as friends, OK?

I think that is a good idea. Now let's get back to topic, shall we?

[Cognizant]

ZrBarnes: As it pertains to NMDA antagonism and it's effects on cognition, I posted another study, along with tons of stuff on D-Serine, Sarcosine, etc. on page 3 of this thread. There seems to be a growing body of evidence for NMDA antagonism having quite a potent nootropic effect in various ways, such as increasing the density of NMDA receptors and helping to prevent stimulant tolerance. Here is a study: http://www.ncbi.nlm....pubmed/22016520

Also, as for all of this research into NMDA receptor activation and what not, it is in my humble opinion that we should be focusing on is not how we can activate receptors per se, but instead focus on receptor modulation - that is to gradually increase the efficiency of our biological learning processes (ie. "I have made my NMDA/AMPA receptor system more efficient and, in a sense, more powerful [ie. more inclined to be activated by stimuli, but not so much that we get heavy excitotoxicity] and I can now put memorize X amount of information in Y amount of time instead of Z amount of time). This is kind of what Psionic is talking about with his usage of MXE, although I am not too keen on using Grey Market drugs.

[unbeatableking]

Pardon if I may: but when I was referring to NMDA-antagonism being counterproductive within the context of an increase in cognition, I was speaking from a short-term perspective.

Yes, it is true that the antagonism of NMDA receptors from a long-term perspective can lead to the upregulation of NMDA receptors.

One of the main symptoms underlying alcohol withdrawals? Seizures - indicative of excess NMDA activity.

The reaction is brought upon by the prolonged downregulation of NMDA receptors. Withdrawing without 'tapering' off can lead to an abrupt rebound.

It is akin to giving your receptors a break and allowing them to re-sensitize, so to speak.

Edited by unbeatableking, 28 August 2012 - 03:50 AM.

[unbeatableking]

BTW, as per your query Psionic.

I'd be wary of first-time dosages. This isn't to say that your anecdote is not truthful, but a lot of people have reported much of the same effect on various types of substances upon taking them for the first time.

And D-serine is an NMDA-receptor agonist, not an NMDA-receptor antagonist.

Although there is a possible recuperative 'synergy', so to speak, when taking NMDA-receptor antagonists during your down-time.

[unbeatableking]

Anyways, there are many positive anecdotes regarding d-serine online.

For those of you who want to know about a possible synergy between D-Aspartic Acid, Sarcosine and D-Serine, I have made an order that should arrive sometime next month, probably the first week of next month.

I will create a comprehensive log and I will try to remain as scientific as possible, for those of you who have questions or requests, feel free to ask them.

I would like to add that I have had many positive effects from taking phosphatidylserine, so it will be interesting to see how a direct metabolite will effect me.

Edited by unbeatableking, 28 August 2012 - 04:22 AM.

[unbeatableking]

There is some merit in the temporary antagonism of NMDA receptors, as the study below should elucidate:

Exposure of cerebellar granule cells to NMDA in culture at 5 days in vitro, when cells are not yet vulnerable to NMDA, evoked a pronounced reduction in NMDA receptor activity, measured by NMDA-induced 45Ca2+ influx, and counteracted the normal developmental increase in NMDA receptors. The effect was concentration and time dependent, the half-maximal effect being reached at about 45 microM and by 4-5 h. The decrease in NMDA receptor function was accompanied by a significant reduction in the protein level of the obligatory NMDA receptor subunit (NR) NR1. Both parameters remained at a low level as long as the agonist was present. However, receptor down-regulation was reversible, as receptor protein levels and NMDA responses were restored to control values upon NMDA removal, this process requiring protein synthesis. NMDA treatment also elicited a decrease in NR1, NR2A, and NR2B subunit messenger RNA (mRNA) levels. However, in comparison with NMDA receptor proteins, the decrease was faster, and NMDA receptor mRNA content recovered to control levels within 24 h in spite of the presence of NMDA. Concerning the mechanisms of agonist-induced regulation of NMDA receptor expression, it seems that protein kinase C-mediated protein phosphorylation is not involved, whereas inhibition of Ca2+/calmodulin-dependent kinase II/IV by KN-62 does depress NMDA receptor expression even in the absence of NMDA.

Although done in vitro, It is apparent that some form of interruption in NMDA activity is necessary for continued NMDA functioning. Mostly as a recuperative aid, giving the receptors a break, in that sense.

Perhaps the discussion can be taken elsewhere, as the topic isn't really in congruence with D-Serine as a supplement as of now however. We have yet to touch on D-serine deeply.

Edited by unbeatableking, 28 August 2012 - 04:09 AM.

[Cognizant]

That is great, unbeatableking, I was hoping that someone would bite the bullet, so to speak, and buy the NMDA agonist stack and be a guinea pig for us Also, I thought that you were referring to the negative (below baseline as you phrased it) effects of NMDA antagonism on learning in the short term; I would not take NMDA antagonists while trying to learn something (although Psionic's experience is anecdotally interesting). I do, however, take NMDA antagonists (ie. Glycine and Magnesium Threonate) at bedtime, when I am not trying to learn anything and, besides definitely helping with sleep, I think that they do have a place in a receptor (AMPA and NMDA) regimen.

My only concern with NMDA antagonism is if they could have a detrimental effect on memory consolidation during sleep (REM specifically, but other cycles as well).

Also, as I have said before, I think that there is much that we can do with receptor modulation (even at this point in time, where there is much in the air about how we are effecting the receptors long-term and, even, short-term). For AMPA receptors: the racetams positively potentiate (usually allosterically) them and Galantamine does so as well (although, in my opinion, it is even better, as it also helps to re sensitize nAChRs) and for NMDA: we have potentially effective agonists, for the daytime, in DAA/D-Serine/Sarcosine and antagonists, for the night/sleep time, in MagT/Memantine.

What we have to do is try to quantify how these things can effect us, relative to our individual NMDA hyper/hypoactivity. For example, in a discussion on the effects of LEF's MagT, someone on this forum said that they took one serving and they had some sort of seizure-like episode and others have said that they can only take 1/3 or so of a serving, or they get too sedated - including effects into the next day. Now, I can, and do, take a full serving of LEF's MagT, 3 grams of Glycine and a serving of ZMA each night and I have not had any negative effects from this, so, clearly, my natural level of NMDA activity is different than the other posters; so, what does that mean? How should each person tailor there supplements accordingly? How can you figure out how much agonism/antagonism you should be shooting for? These are some of the questions that we need to answer, to best benefit everyone.

[unbeatableking]

^

I don't recommend people try the stack mentioned, 'unprepared', so to speak.

D-Aspartic Acid is a testosterone/estrogen booster used primarily by bodybuilders. Those who suffer from a genetic predisposition towards gynecomastia and other more endocrinological issues should probably stick to D-Serine.

In addition, the mean recommended 'usage' period for the DAA stack averages between one to two months. Which means that it isn't viable in the long-term.

I will probably get blood panels done in order to see the effect the stack might have on my hormones.

[unbeatableking]

Some of these purported 'endocrinological' side-effects as brought upon by DAA include (albeit, anecdotally) variances in libido, an increase in acne and nipple issues.

This isn't to say that the stack is 'dangerous', but some people just generally have hormonal profiles that make them prone to such issues. There are many positive reports regarding the stack, without any of the side-effects associated, in addition.

Needless to say, although some might call this paranoia: I am going to order an aromatase inhibitor in the event of such issues occurring.

[Cognizant]

I agree, unbeatableking, I am not recommending anyone jumping on the stack that I just mentioned either. What I am saying, personally, is that we have a lot of tools to work with and, as should always be recommended, start out small. So, for example, I have been using NMDA antagonists for awhile, with no negative side effects, so, once you have reported back on the, hopefully , positive effects of DAA/Sarcosine/D-Serine, I would like to move onto using some NMDA agonists during the day. As for AMPA, many of us on this forum have experience with Pi/Ani/Oxiracetam and/or Galantamine and so it is not much of a stress to assume that we could figure that aspect (ie. modulation of AMPA receptors) as well and make this more synergical (is that a word? ).

[metaprog]

No but synergistic is

Just ordered D-Serine from SP. Decided to go with SP over PN because it seemed to me that they disclose more information about the product upfront. And for the same price, SP offers 100g whereas PN offers 90g per bottle. I've been supplementing with DAA for the past 2 weeks...I did write briefly on my experience in another thread for those who are curious. Like most, I'm extremely interested to see what type of synergistic effect I get from stacking DAA w/D-Serine. One would heuristically think that simultaneous activation of both co-agonist sites could provide a potent & noticeable effect. We shall see. I'll report back with my findings.

http://www.longecity...dar-activation/

[unbeatableking]

^

A word of advice: I'd start with just the D-Serine first.

Just to see how it stands out. We also want to flesh out any extraneous variables.

[ScienceGuy]

Irish MD,

I'm confused regarding D-SERINE's precise mechanism of action at the respective NMDA RECEPTOR; and I believe that it would benefit everyone (both healthy individuals and those with relevant pre-existing health conditions such as myself) if you can be kind enough to clarify matters.

Specifically my confusion lies within these two seemingly contradictory statements of yours (wherein my confusion is almost certaining due to my misunderstanding, as opposed to any error on your part):

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.

...D-Serine doesn't predispose to excitotoxicity even in the presence of some imagininary illness (even if it were real), because of the dynamics of the compound with its receptor. D-Serine is a co-agonist, and requires numerous criteria to be met prior to agonism. In humans and higher mammals, it requires preceeding agonism of the AMPA receptor, membrane depolarization, NMDA magnesium displacement, and accompanying binding with glutmate (or DAA/NMDA). It gets more complicated from here (receptor autoregulation, increased membrane electrical potential) but I won't confuse you. Thus, even supraphysiological levels of D-Serine will not activate the receptor. In mice, glutaminergic receptor dynamics are different (and you would know that if you had any actual scientific education). Taking DAA with D-serine still does not predispose to excitotoxicity because DAA has no affinity for the AMPA receptor.

So, here's what is confusing me and likely wherein lies my misunderstanding... On the one hand you state that D-SERINE produces NOOTROPIC effects via its activation of the NMDA RECEPTOR; but then on the other hand you state that D-SERINE cannot activate the NMDA RECEPTOR... Both these statements cannot be correct, no?

If you can please be kind enough to clarify exactly what's going on here, and hence how I am misunderstanding matters, I would most greatly appreciate it

You will have to excuse my confusion since my understanding of BIOCHEMISTRY is not as comprehensive as yours

Edited by ScienceGuy, 01 September 2012 - 08:40 AM.