88 replies to this topic

[Area-1255]

Yes, from my own experience also it is very clear that we don't want our NMDA receptors to be antagonized and instead we want them to be activated and functional. It seems to be a key switch in the brain that turns everything else on.

 

 

My quest is to find a sustainable way to upregulate and stimulate those receptors. You say antagonism is bad but my idea has always been that using an NMDA antagonist might lead to upregulation in the long run. You yourself mentioned that we should try to predict the homeostatic response of the body. Wouldn't agonizing with sarcosine or anything else lead to downregulation in the long term?

 

DHEA, PREGNENOLONE; take those as positive allosteric modulators of NMDA-glutamate receptors, and yes, blocking NMDA may worsen OCD for many. Agonizing it should help both schizophrenia and OCD.

 

DIHYDROTESTOSTERONE; as shown below, upregulates NMDA and increases binding...thus

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THE ANSWER TO ACTIVATING AND UPREGULATING NMDA IS....

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DHT, PREGNENOLONE, AND DHEA....good for anxiety, OCD, depression, libido etc

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• Use creatine and protodioscin to boost DHT naturally.
• You can easily buy pregnenolone and DHEA for cheap online.

 

 

 

http://molpharm.aspe...ontent/40/3/333

http://en.wikipedia....anism_of_action

Book on NeuroSteroids ; NMDA SECTION

 

Endocrinology. 2005 Apr;146(4):2091-7. Epub 2005 Jan 20.

Dihydrotestosterone increases hippocampal N-methyl-D-aspartate binding but does not affect choline acetyltransferase cell number in the forebrain or choline transporter levels in the CA1 region of adult male rats.

Romeo RD1, Staub D, Jasnow AM, Karatsoreos IN, Thornton JE, McEwen BS.

Author information

 

Abstract

Testosterone, acting through its androgenic metabolite 5alpha-dihydrotestosterone (DHT), can increase dendritic spine density in the CA1 region of the male rat hippocampus. The mechanisms mediating this increase in spines are presently unknown. In female rats, estrogen (E) has been shown to increase spine density, which is in part mediated by increases in N-methyl-d-aspartate (NMDA) receptors in the CA1 region and cholinergic forebrain inputs to the hippocampus. Whether similar mechanisms are responsible for the DHT-induced increase in spines in the male remains to be determined. In the first experiment, we used [(3)H]glutamate NMDA receptor binding autoradiography to assess whether DHT-treated males had higher NMDA receptor levels in the CA1 region of the hippocampus, compared with oil-treated males. In the second set of experiments, we used choline acetyltransferase (ChAT) in situ hybridization and immunohistochemistry to assess whether DHT could affect ChAT cell number in the forebrain. We also investigated the effect of DHT on hemicholinium-3-sensitive choline transporter levels in the CA1 region of the male hippocampus. We found that DHT significantly increased NMDA receptor binding in the CA1 region of males but had no effect on ChAT cell number in the forebrain or hemicholinium-3-sensitive choline transporter protein levels in the CA1 region. These data indicate that, similar to E-induced spinogenesis in females, DHT-induced increases in spine formation in males may require increases in NMDA receptors. However, unlike E-treated females, these data suggest that DHT does not influence cholinergic inputs to the hippocampus.

PMID:   15661864   [PubMed - indexed for MEDLINE]

[Area-1255]

here's a brand new article on this subject... 

How to Upregulate NMDA Receptors and Boost Their Function (Also Discussing Positive Allosteric Modulators of NMDA)

[Area-1255]

Any other ideas for NMDA upregulation, lemme know...so I can add it to the article. GLY-1 seems to be a good target as well.

http://www.ncbi.nlm....les/PMC3023951/

http://www.google.co...s/US20050267152

[Flex]

sodium benzoate via d-serine degradation inhibition.

The advantage is afaik that the partial agonsim do prevent or slow the downregulation

Edited by Flex, 10 January 2015 - 08:02 PM.

[Area-1255]

sodium benzoate via d-serine degradation inhibition.

The advantage is afaik that the partial agonsim do prevent or slow the downregulation

Yeah, that's a mechanism the anti-psychotic risperdal shares as well.

 

 

J Psychopharmacol. 2010 Jul;24(7):1055-67. doi: 10.1177/0269881109102644. Epub 2009 Mar 27.

The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia.

Abou El-Magd RM1, Park HK, Kawazoe T, Iwana S, Ono K, Chung SP, Miyano M, Yorita K, Sakai T, Fukui K.

Author information

 

Abstract

D-Amino acid oxidase (DAO) has been established to be involved in the oxidation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia. The effect of risperidone, a benzisoxazole derivative, atypical antischizophrenic drug, on the activity of human DAO was tested using an in-vitro oxygraph system and rat C6, stable C6 transformant cells overexpressing mouse DAO (designated as C6/DAO) and pig kidney epithelial cells (LLC-PK(1)). Risperidone has a hyperbolic mixed-type inhibition, designated as 'partial uncompetitive inhibition effect', with K(i) value of 41 microM on human DAO. Risperidone exhibited a protective effect from D-amino acid induced cell death in both C6/DAO and LLC-PK(1) cells with 10% increase in viability. These data indicate the involvement of DAO activity in D-serine metabolism and also suggest a new mechanism of action to risperidone as antischizophrenic drug.

Comment in

So risperdal boosts glutamate at the NMDA receptor, in addition to blocking multiple serotonin receptors and such....seems like risperidone's anti-psychotic actions come more from it's glutamatergic activity.

[Flex]

For what is this good ?

Afaik, even by taking low doses, Risperdal would still exert sooner or later a months lasting dopamine receptor reduction.

[Area-1255]

For what is this good ?

Afaik, even by taking low doses, Risperdal would still exert sooner or later a months lasting dopamine receptor reduction.

Oh nothing, it's terrible, I'm just pointing out that this is a shared MOA.

[Flex]

I´ve just wrote for the case that You or anyone else wasnt aware of that.

[MichaelTheAnhedonic]

I'm sorry for interrupting but 1 question... Can it be the cause of my very annoying tinnitus and ALL negative symptoms (extreme apathy, no thoughts in my head...)? 

[Area-1255]

I'm sorry for interrupting but 1 question... Can it be the cause of my very annoying tinnitus and ALL negative symptoms (extreme apathy, no thoughts in my head...)? 

Yes, NMDA and tinnitus are linked.

In addition, both high and low histamine can cause Meniere's Disease type symptoms, with a focus on and trend towards lower histamine types (and high copper levels predominating).

Betahistine and ginkgo biloba are the two best treatments for meniere's. 

If you need a local source for betahistine, though I'm in the USA; just PM me.

I have access to a lab that makes it.

 

Neural Plast. 2007;2007:80904. doi: 10.1155/2007/80904.

Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma.

Guitton MJ1, Dudai Y.

Author information

 

Abstract

Tinnitus, the perception of sound in the absence of external acoustic stimulation, is a common and devastating pathology. It is often a consequence of acoustic trauma or drug toxicity. The neuronal mechanisms of tinnitus are neither yet fully understood nor are effective treatments available. Using a novel behavioral paradigm for measuring tinnitus in the rat based on tone-guided navigation, we show here that the development of long-term noise-induced tinnitus, the most prevalent and clinically important form of human tinnitus, can be abated by local administration of the NMDA antagonist "ifenprodil" into the cochlea in the first 4 days following the noise insult but not afterwards. This suggests that long-term tinnitus undergoes a consolidation-like process, resembling the ontogeny of items in long-term memory. Furthermore, this finding paves the way to potential therapeutic strategies for the prevention of chronic tinnitus once the noise insult had taken place.

https://pubpeer.com/...B95606275D10712

"Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma"

 

Use of an nmda receptor antagonist the treatment of tinnitus induced by cochlear excitotoxicity

 

 

 

WO 2007119098 A2

ABSTRACT

The invention relates to methods for the prevention and/or treatment of tinnitus induced by cochlear excitotoxicity. In these methods, a pharmaceutical composition comprising an NMDA receptor antagonist is administered to an individual in need of such treatment by appropriate devices and/or formulations for local administration to the inner ear. The tinnitus to be prevented and/or treated may be provoked by acoustic trauma, presbycusis, ischemia, anoxia, treatment with one or more ototoxic medications, sudden deafness, or other cochlear excitotoxic-inducing occurrence. The invention also relates to method for the identification of compounds effective in the treatment and prevention of tinnitus by a novel screening method incorporating an electrophysiological test method.

 

 

http://www.google.co...7119098A2?cl=en

Edited by Area-1255, 11 January 2015 - 02:45 AM.

[MichaelTheAnhedonic]

Interesting, thanks. But I already tried sarcosine, glycine and D-aspartic-acid - nothing. 

[Area-1255]

Interesting, thanks. But I already tried sarcosine, glycine and D-aspartic-acid - nothing. 

What  effects did you get, anything at all? I loved DAA, especially with conessine or an H3 antagonist, histamine and glutamate tend to work together while histamine can, in some instances, protect against excito-toxicity of glutamate and re-direct the extra glutamate in the right areas. This is thought to be through histamine enhancement of GABA which then modulates glutamate downstream / directly.

[MichaelTheAnhedonic]

Nothing at all. I hope that it is not frontal lobe atrophy.

[Area-1255]

Nothing at all. I hope that it is not frontal lobe atrophy.

Check your PMs,

[Flex]

If someone is interrested, Bacopa monnieri increased a Glutamate transporter in the hippocampus (VGlut1)

 

Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and VGLUT1 density in the prefrontal cortex, striatum, and hippocampus of sub-chronic phencyclidine rat model of schizophrenia.

http://www.ncbi.nlm....pubmed/23745319

 

[Area-1255]

If someone is interrested, Bacopa monnieri increased a Glutamate transporter in the hippocampus (VGlut1)

 

Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and VGLUT1 density in the prefrontal cortex, striatum, and hippocampus of sub-chronic phencyclidine rat model of schizophrenia.

http://www.ncbi.nlm....pubmed/23745319

Very very interesting, thanks for this Flex!

[Flex]

[Area-1255]

[Nordmann]

So Tribulus Terrestris, Creatin, Pregnenolone and DHEA? When and what are your recommended dose? 

 

[Area-1255]

 

So Tribulus Terrestris, Creatin, Pregnenolone and DHEA? When and what are your recommended dose? 

 

 

Creatine; 2-10 grams a day, tribulus, depends on which extract, and how much protodioscin. Pregnenolone/DHEA, best recommend Preg be in a higher dose than DHEA if you are prone to anxiety disorders, but if you have high cortisol, then emphasize a higher dose of DHEA.

[Nordmann]

So I`ve taken 30mg Preg, 25mg Dhea and 1g Tribulus for a little while with my regular Ciltep. I know, debunked, but it still has a profound effect on me.

I like this, very clearheaded, high mood, memory and more. I have stopped night sweating and don`t sweat as much on workouts. Very determined, following my diet to point, not taken a chocolate, drink, smoke or joint since I started, about 20 days. I`m not stopping these things, just aint craving it. 

 

Pregnenolone has a great reputation and well deserved in my opinion. I feel a bit rebooted, I experienced with different anabolic steroids in my youth with heavy drinking and cannabis abuse. And then years with heavy exercise, up to 3 workouts a day. Should put a strain on my hormones. 

 

Everything is very nice and dandy these days. Only thing I have noticed is that my brain needs more choline to keep my intensity up. I was pretty sensitive to choline before, it often induced a depressive state. But now my brain love it. 

 

So thanks for this thread

 

 

[Area-1255]

So I`ve taken 30mg Preg, 25mg Dhea and 1g Tribulus for a little while with my regular Ciltep. I know, debunked, but it still has a profound effect on me.

I like this, very clearheaded, high mood, memory and more. I have stopped night sweating and don`t sweat as much on workouts. Very determined, following my diet to point, not taken a chocolate, drink, smoke or joint since I started, about 20 days. I`m not stopping these things, just aint craving it. 

 

Pregnenolone has a great reputation and well deserved in my opinion. I feel a bit rebooted, I experienced with different anabolic steroids in my youth with heavy drinking and cannabis abuse. And then years with heavy exercise, up to 3 workouts a day. Should put a strain on my hormones. 

 

Everything is very nice and dandy these days. Only thing I have noticed is that my brain needs more choline to keep my intensity up. I was pretty sensitive to choline before, it often induced a depressive state. But now my brain love it. 

 

So thanks for this thread

No problem , friend. Glad to help!

[iseethelight]

Amazing thread Area.

During my routine research for my cure last night, I've come to realize that I may have a low NMDA activity disorder causing very low glutamate and gaba production thus causing several neurotransmitters to get outta control when I take precursors or consume too much in the diet. That is why choline, tyrosine, 5htp, tryptophan, theanine all have very adverse side effects on me along with some benefits. There is no Gaba to control their flow in my brain. Piracetam is the only thing that has had positive effects on me but they only last a few days. I know that piracetam's main action is on the glutamate receptors.

 

I've started taking l glutamine, and will start D-aspartic acid asap. I wish there was a good, guaranteed way to safely increase NMDA receptor activities. At this stage I don't care about killing neurons, I just want to be normal with normal memory and motivation, and pleasure sensors. I can't live like this.

Edited by iseethelight, 01 November 2015 - 06:21 PM.

[kurdishfella]

is Low NMDA-Receptor Activity common or rare? also can it cause excess serotonin levels? also what about high NMDA-receptor activity? is that a thing what can that cause?

 

[jack black]

common knowledge is NMDA overactivity = excitotoxicity

[kurdishfella]

@jackblack Does low or high NMDA Cause excess serotonin?

Edited by farshad, 09 December 2017 - 12:57 AM.

[Lifemap]

So if low NMDA activity causes a myriad of undesirable symptoms " ahedonia/dysphoria can be possible, DEpersonalization and delirium, along with other classic low glutamate symptoms such as Insomnia, Fatigue etc ...and feeling like people are reading your thoughts, usually coupled with paranoia."

 

How is it that ketamine a NMDA antagonist can help ameliorate symptoms such as depression/anhedonia, anxiety , many of which are syptoms of long periods of high stress and or PTSD.  From my limited understanding NMDA antagonist reduce glutamate. https://www.research...of_dissociation

Yet I'm reading that we want an NMDA agonist instead?  

Edited by Lifemap, 07 April 2018 - 06:48 AM.

[Galaxyshock]

NMDA activation amplifies experience, the sensations and feelings. It can cause negative emotions to feel absolutely horrible agony. A single negative event can send you to awful depressive state as NMDA rapidly programs it to your brain.

[CarlSagan]

So if low NMDA activity causes a myriad of undesirable symptoms " ahedonia/dysphoria can be possible, DEpersonalization and delirium, along with other classic low glutamate symptoms such as Insomnia, Fatigue etc ...and feeling like people are reading your thoughts, usually coupled with paranoia."

 

How is it that ketamine a NMDA antagonist can help ameliorate symptoms such as depression/anhedonia, anxiety , many of which are syptoms of long periods of high stress and or PTSD.  From my limited understanding NMDA antagonist reduce glutamate. https://www.research...of_dissociation

Yet I'm reading that we want an NMDA agonist instead?  

 

Maybe theraputic doses causes upregulation of NMDA receptors. but thread is aimed at people who have hypoactive NMDA activity, maybe these people don't or are on the high side so antagonizing isnt a problem? or could be another mechanism. 


Interesting thread. Zinc gives me extreme incessant thinking / anxiety interfering with sleep, to the point where I couldnt imagine why its part of peoples sleep stacks. and surprisingly moderate doses of magnesium ramps up excessive mind & induces some sort of tiredness, but paradoxically gives me insomnia. which is the opposite of what most people report.

 

1 thing in common with both zinc & mag is they're antagonistic to NMDA. now i'm curious about trying the opposite to see if there's opposite effects (lessened anxiety, ocd thinking, better sleep etc). will give DAA a test.

Edited by CarlSagan, 17 August 2021 - 04:11 PM.