23 replies to this topic

[medievil]

There's been alot of intrest in this lately, also because glutamate hypoactivity is implicated in a bunch of disorders.

Some previeus threads about this:
http://www.longecity...ropic-d-serine/
http://www.longecity...dar-activation/

Glutamate is the main neurotransmitter in the brain and regulates pretty much all neurotransmitters and indeed glutaminergic issues are involved in a whole list of mental disorders.

It appears that ADHD, AVPD, OCD, BDD and depression can be caused by glutamate hypoactivity, i made this thread to start a discussion focussing on this with potential treatments and hopefully some succesfull anecdotes.

As for my personal experience sarcosine (a glycine reuptake inhibitor) worked damn well for my OCD:

"Sarcosine therapy for obsessive compulsive disorder: a prospective, open-label study.
Wu PL, Tang HS, Lane HY, Tsai CA, Tsai GE.
Source
Department of Psychiatry, China Medical University Hospital, Taichung, Taipei, Taiwan.
Abstract
BACKGROUND:
Several lines of evidence implicate glutamatergic neurotransmission in the pathophysiology of obsessive compulsive disorder (OCD). Sarcosine is an endogenous antagonist of glycine transporter-1. By blocking glycine uptake, sarcosine may increase the availability of synaptic glycine and enhance N-methyl-d-aspartate (NMDA) subtype glutamatergic neurotransmission. In this 10-week open-label trial, we examined the potential benefit of sarcosine treatment in OCD patients.
METHOD:
Twenty-six outpatients with OCD and baseline Yale-Brown Obsessive Compulsive Scale (YBOCS) scores higher than 16 were enrolled. Drug-naive subjects (group 1, n = 8) and those who had discontinued serotonin reuptake inhibitors for at least 8 weeks at study entry (group 2, n = 6) received sarcosine monotherapy. The other subjects (group 3, n = 12) received sarcosine as adjunctive treatment. A flexible dosage schedule of sarcosine 500 to 2000 mg/d was applied. The primary outcome measures were Y-BOCS and Hamilton Anxiety Inventory, rated at weeks 0, 2, 4, 6, 8, and 10. Results were analyzed by repeated-measures analysis of variance.
RESULTS:
Data of 25 subjects were eligible for analysis. The mean ± SD Y-BOCS scores decreased from 27.6 ± 5.8 to 22.7 ± 8.7, indicating a mean decrease of 19.8% ± 21.7% (P = 0.0035). Eight (32%) subjects were regarded as responders with greater than 35% reduction of Y-BOCS scores. Five of the responders achieved the good response early by week 4. Although not statistically significant, drug-naive (group 1) subjects had more profound and sustained improvement and more responders than the subjects who had received treatment before (groups 2 and 3). Sarcosine was tolerated well; only one subject withdrew owing to transient headache.
CONCLUSION:
Sarcosine treatment can achieve a fast therapeutic effect in some OCD patients, particularly those who are treatment naive. The study supports the glycine transporter-1 as a novel target for developing new OCD treatment. Large-series placebo-controlled, double-blind studies are recommended."

"Neural Plast.
2009;2009:768398. Epub 2010 Feb 18.
High-dose glycine treatment of refractory obsessive-compulsive disorder and body dysmorphic disorder in a 5-year period.

Cleveland WL, DeLaPaz RL, Fawwaz RA, Challop RS.
Source

Department of Medicine, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, NY 10019, USA. WLC1@columbia.edu


Abstract


This paper describes an individual who was diagnosed with obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD) at age 17 when education was discontinued. By age 19, he was housebound without social contacts except for parents. Adequate trials of three selectiveserotonin reuptake inhibitors, two with atypical neuroleptics, were ineffective. Major exacerbations following ear infections involving Group A beta-hemolytic streptococcus at ages 19 and 20 led to intravenous immune globulin therapy, which was also ineffective. At age 22, another severe exacerbation followed antibiotic treatment for H. pylori. This led to a hypothesis that postulates deficient signal transduction by the N-methyl-D-aspartate receptor (NMDAR). Treatment with glycine, an NMDAR coagonist, over 5 years led to robust reduction of OCD/BDD signs and symptoms except for partial relapses during treatment cessation. Education and social life were resumed and evidence suggests improved cognition. Our findings motivate further study of glycine treatment of OCD and BDD."

"J Clin Psychiatry.
2009 Nov;70(11):1530-5. Epub 2009 Jun 30.
Double-blind study of dextroamphetamine versus caffeine augmentation for treatment-resistant obsessive-compulsive disorder.

Koran LM, Aboujaoude E, Gamel NN.
Source

OCD Clinic, Stanford, CA 94305, USA. lkoran@stanford.edu


Abstract

INTRODUCTION:

Two small, double-blind, placebo-controlled, single-dose, crossover studies found dextroamphetamine (d-amphetamine) 30 mg clearly superior to placebo in relieving symptoms of obsessive-compulsive disorder (OCD). We conducted a 5-week, double-blind, caffeine-controlled study to test the hypothesis that d-amphetamine, added after an adequate selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) trial, would be more effective than caffeine in reducing residual OCD symptoms of moderate or greater severity.
METHOD:

Between August 2006 and February 2008, we enrolled adults with DSM-IV OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of >or= 20 after >or= 12 weeks of adequate treatment with an SSRI or SNRI. Subjects were randomly assigned to double-blind d-amphetamine 30 mg/d or caffeine 300 mg/d added to their SSRI/SNRI and other medications. Responders (first week mean Y-BOCS score decrease of >or= 20%) entered the study's 4-week double-blind extension phase.
RESULTS:

We enrolled 24 subjects, 11 women and 13 men, with a mean (SD) age of 40 (13.2) years and mean baseline Y-BOCS scores of 26.5 (4.1) for the d-amphetamine group (n = 12) and 29.1 (4.0) for the caffeine group (n = 12). At the end of week 1, 6 of 12 d-amphetamine subjects (50%) and 7 of 12 caffeine subjects (58%) were responders. At week 5, the responders' mean Y-BOCS score decreases were, for the d-amphetamine group (last observation carried forward), 48% (range, 20%-80%); and, for the caffeine group, 55% (range, 27%-89%). Obsessive-compulsive disorder and depression improvement were independent. The double-blind remained intact. No subject discontinued the study due to side effects.
CONCLUSIONS:

Larger, double-blind, placebo-controlled trials of both d-amphetamine and caffeine augmentation are needed in OCD subjects inadequately responsive to adequate doses of an SSRI or SNRI.
TRIAL REGISTRATION:
"
I also included that study on amphetamine, it releases glutamate and d serine and in my case completely abolished my ocd in contrast to DRI's.

[abelard lindsay]

This led to a hypothesis that postulates deficient signal transduction by the N-methyl-D-aspartate receptor (NMDAR). Treatment with glycine, an NMDAR coagonist, over 5 years led to robust reduction of OCD/BDD signs and symptoms except for partial relapses during treatment cessation. Education and social life were resumed and evidence suggests improved cognition. Our findings motivate further study of glycine treatment of OCD and BDD."

Good find.. Glycine has been a good addition to my stack for improvement in the stroop test.

I think there might be a link here between OCD and fluid intelligence deficiencies. For instance:

http://www.ncbi.nlm....pubmed/19081580

Combined with functional imaging method, we applied neuropsychological batteries to demonstrate a working memory deficit in OCD by comparison with normal controls. In addition, working memory and brain activation were further examined with symptom-based analysis. Forty patients with OCD and 25 normal controls were examined using neuropsychological tests including the WAIS-R, WCST, WMS-R, and R-OCFT and functional MRI (fMRI) during the N-back task including 0- and 2-back task. On fMRI, the brain regions activated during the performance and the differences in the activation between patients and controls were identified. Additional analyses of severity and subtypes were conducted by using Y-BOCS severity score, symptom-checklist and Leckman's four-factor model, respectively. On the neuropsychological tests, the OCD patients had significantly lower scores on the delayed recall section of the WMS-R and the immediate recall section of the R-OCFT compared to the controls

[Psionic]

so sarcosine, d-serine, glycine, amps, ketamine or low dose psilocybe mushrooms all can have similar effects on those disorders? I think that at least three last have profound effect on cognition. And I still wonder if d-serine is superior to sarcosine or not.

[khemix]

if glutamate hypoactivity is the problem, why do you so strongly push memantine?

[medievil]

if glutamate hypoactivity is the problem, why do you so strongly push memantine?

I no longer take memantine, i however still strongly support it for the use of tolerance prevention, its also effective against shizophrenia, OCD and other disorders but going the other route (glutamate potentiation) is more effective in many cases.

[khemix]

i have ocd, so which is more effective? memantine or something that potentiates glutamate?

[medievil]

Its individual too, i found both mem and sarcosine effective but liked sarcosine a ton more.

If your also into cognitive enhancement, try sarcosine first.

[CIMN]

Its individual too, i found both mem and sarcosine effective but liked sarcosine a ton more.

If your also into cognitive enhancement, try sarcosine first.

i dont get it, how is glycine good for cognition if it acts as a inhibitory neurotransmitter. it activates glutmate receptors and acts inhibitory??

[gizmobrain]

I think the confusion lies in the fact that most brief descriptions of glycine only talk of it in terms of inhibition, however not all glycine receptors are inhibitory. Glycine (or D-serine) is a necessary co-agonist (along with glutamate) for the activation of NMDA sites.

There is also a difference between pre- and post- synaptic glycine receptors:

Glycine and GABAA (g-aminobutyric acid A) receptors are inhi- bitory neurotransmitter-gated Cl− channels localized in post- synaptic membranes. In some cases, GABAA receptors are also found presynaptically, but they retain their inhibitory effect as their activation reduces excitatory transmitter release1±4. Here we report evidence for presynaptic ionotropic glycine receptors, using pre- and postsynaptic recordings of a calyceal synapse in the medial nucleus of the trapezoid body (MNTB). Unlike the classical action of glycine, presynaptic glycine receptors triggered a weakly depolarizing Cl− current in the nerve terminal. The depolarization enhanced transmitter release by activating Ca2+ channels and increasing resting intraterminal Ca2+ concentra- tions. Repetitive activation of glycinergic synapses on MNTB neurons also enhanced glutamatergic synaptic currents, indicat- ing that presynaptic glycine receptors are activated by glycine spillover. These results reveal a novel site of action of the transmitter glycine, and indicate that under certain conditions presynaptic Cl− channels may increase transmitter release.

→ source (external link)

[CIMN]

zrbarnes thanks

[gizmobrain]

Lots of goodies need to be unpacked from these studies:

http://www.ncbi.nlm....cles/PMC3350466
http://www.ncbi.nlm....cles/PMC2954603

And here is another study of interest, the role of zinc on glycine modulation:

Glycine' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118471']Glycine receptors are widely expressed in the mammalian central nervous system, and previous studies have demonstrated that glycine receptors are modulated by endogenous zinc. Zinc is concentrated in synaptic vesicles in several brain regions but is particularly abundant in the hippocampus and olfactory bulb. In the present study, we used patch-clamp electrophysiology of rat hippocampal and olfactory bulb neurons in primary culture to examine the effects of zinc on glycine receptors. Although glycine has been reported to reach millimolar concentrations during synaptic transmission, most previous studies on the effects of zinc on glycine receptors have used relatively low concentrations of glycine. High concentrations of glycine cause receptor desensitization. Our current results extend our previous demonstration that the modulatory actions of zinc are largely prevented when co-applied with desensitizing concentrations of glycine (300 μM), suggesting that the effects of zinc are dependent on the state of the receptor. In contrast, pre-application of 300 μM zinc, prior to glycine (300 μM) application, causes a slowly developing inhibition with a slow rate of recovery, suggesting that the timing of zinc and glycine release also influences the effects of zinc. Furthermore, previous evidence suggests that synaptically released zinc can gain intracellular access, and we provide the first demonstration that low concentrations of intracellular zinc can potentiate glycine receptors. These results support the notion that zinc has complex effects on glycine receptors and multiple factors may interact to influence the efficacy of glycinergic transmission.

→ source (external link)

Edited by zrbarnes, 06 August 2012 - 10:48 PM.

[Thorsten3]

Yes for Sarcosine, with it being a glycine reuptake inhibitor this helps activate the NMDA receptor which should increase glutamate transmission. It would be more efficacious than glycine itself (you have to take stupid amounts for NMDA activation).

I've tried Sarcosine and I liked it. Dramatic decrease in OCD and increased libido slightly, also improved hedonic tone slightly. I never noticed anything cognitive though. It also had a weird effect on my sleeping pattern (strongly initiating sleep but would make it a bitch to get up the following morning). This was the reason I stopped it.

Sarcosine is fairly cheap at SmartPowders.

[khemix]

Its individual too, i found both mem and sarcosine effective but liked sarcosine a ton more.

If your also into cognitive enhancement, try sarcosine first.

I already take TMG and glycine.

Why did you give up on memantine though? You were one of the reasons I started to use it. Besides in theory it should synergize with glycine as memantine is dislodged when activated by two agonists. What I didn't like about memantine was that it screwed my memory and made me slower. I don't just mean the first 2 week dissociative phase, it was there for a month. I was up to 20mg/day and reading and learning was just hard. It also stopped stimulants from working as in they no longer gave me effects. I wanted to start it up again and give it atleast 6 weeks to improve cognition but you quitting has me discouraged.

Edited by khemix, 07 August 2012 - 03:04 PM.

[medievil]

I gave it up after i discovered i was in predromal shizophrenia wich is caused by glutamate hypoactivity, i still love memantine but its just not the best option for me.

[jonathan-g]

Doesn't increasing glutamergic activity also cause excitotoxicity?

[chziime]

Yes, I am wondering about the same things. I've been on Memantine 15mg/day for almost half a day, and it is great for my anxiety, especially physical, but I stopped because I wanted to try Sarcosine, as I was getting depersonalized, detached, etc on Memantine. After I stopped, anxiety came back in full force, but I'm still giving Sarcosine a trial.

[Thorsten3]

Doesn't increasing glutamergic activity also cause excitotoxicity?

No. Glutamatergic function is crucial for your brain to function at all. Wihout it, our brains wouldn't even operate. It's like the 'on' switch to everything. So if glutamatergic function is comprimised, like it is in schizophrenia, this causes things to go horribly wrong in many directions (and brain disorders such as schizo can ensue).

AFAIK, excessive glutamatergic function does have the capability of causing excitotoxicity but 'optimizing the glutamatergic system' is a completely different thing. Optimizing it, is a very good thing if you want to lead a good quality of life.

I personally have seen great benefits from sarcosine. it has a wonderful effect on my negative symptons. It is also great for anyone who suffers with panic reactions.

[Reformed-Redan]

Doesn't increasing glutamergic activity also cause excitotoxicity?

No. Glutamatergic function is crucial for your brain to function at all. Wihout it, our brains wouldn't even operate. It's like the 'on' switch to everything. So if glutamatergic function is comprimised, like it is in schizophrenia, this causes things to go horribly wrong in many directions (and brain disorders such as schizo can ensue).

AFAIK, excessive glutamatergic function does have the capability of causing excitotoxicity but 'optimizing the glutamatergic system' is a completely different thing. Optimizing it, is a very good thing if you want to lead a good quality of life.

I personally have seen great benefits from sarcosine. it has a wonderful effect on my negative symptons. It is also great for anyone who suffers with panic reactions.

True dat. Excessive glutamate activity has been shown to cause autism or aspergers syndrome. Aspergers and schizo are in the same spectrum of disorders. Interesting how a slight imbalance in glutamate activity leads to these disorders. Obviously NMDA regulates most of it. Also, excessive glutamate activity leads to anxiety and depression from what I recall, though this has more to do with the glutamate system and GABA. Obviously there are other downstream effects and genetic variances in protein expression that causes the afformentioned disorders, so its not so easy to just increase glutamate activity and all of a sudden you are "normal." Psychiatry has still yet to definite a "normal" person since it almost exclusively deals with abnormal cases.

[lourdaud]

Can anyone think of any good way to increase both glutaminergic and gabaergic tone?

[Mnemonicsmoke]

Can anyone think of any good way to increase both glutaminergic and gabaergic tone?

Not as far as I know, since GABA and Glutamate are sort of on the opposite sides of the scales. In a more literal way GABA is made from Glutamate and Glutamate is made from GABA, it therefore seems very difficult if not impossible to raise both neurotransmitters higher than normal. 

[YoungSchizo]

 

Can anyone think of any good way to increase both glutaminergic and gabaergic tone?

Not as far as I know, since GABA and Glutamate are sort of on the opposite sides of the scales. In a more literal way GABA is made from Glutamate and Glutamate is made from GABA, it therefore seems very difficult if not impossible to raise both neurotransmitters higher than normal. 

 

 

So in my case (schizophrenia) I can say that my brain is hypoactive in Glutamate but it gets (almost) normal levels in Glutamate when taken (a GABA enhancer) Clonazepam?

 

Also, I'm on Sarcosine for 4 years, one of the most potent and cleanest supplement I have ever taken, are there no new potent supps discovered that activate the same system? 

[iseethelight]

 

 

 

So in my case (schizophrenia) I can say that my brain is hypoactive in Glutamate but it gets (almost) normal levels in Glutamate when taken (a GABA enhancer) Clonazepam?

 

Also, I'm on Sarcosine for 4 years, one of the most potent and cleanest supplement I have ever taken, are there no new potent supps discovered that activate the same system? 

 

 

What do you mean by cleanest supplement? Elaborate @youngschizo..

[gamesguru]

good way to increase both glutaminergic and gabaergic tone?

 

The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors.
Musazzi L1, Treccani G, Mallei A, Popoli M. (2013)

Recent compelling evidence has suggested that the glutamate system is a primary mediator of psychiatric pathology and also a target for rapid-acting antidepressants. Clinical research in mood and anxiety disorders has shown alterations in levels, clearance, and metabolism of glutamate and consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these as major factors in psychopathology. Enhancement of glutamate release/transmission, in turn induced by stress/glucocorticoids, seems crucial for structural/functional changes. Understanding mechanisms of maladaptive plasticity may allow identification of new targets for drugs and therapies. Interestingly, traditional monoaminergic-based antidepressants have been repeatedly shown to interfere with glutamate system function, starting with modulation of N-methyl-D-aspartate (NMDA) receptors. Subsequently, it has been shown that antidepressants reduce glutamate release and synaptic transmission; in particular, it was found antidepressants prevent the acute stress-induced enhancement of glutamate release. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression models. Finally, a number of studies over the years have shown that these drugs regulate glutamate receptors, reducing the function of NMDA receptors, potentiating the function of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, and, more recently, exerting variable effects on different subtypes of metabotropic glutamate receptors. The development of NMDA receptor antagonists has opened new avenues for glutamatergic, rapid acting, antidepressants, while additional targets in the glutamate synapse await development of new compounds for better, faster antidepressant action.

The GABA_Breceptor as a target for antidepressant drug action
Subroto Ghose,1 Michelle K Winter,2,3 Kenneth E McCarson (2011)

Preclinical and clinical data suggest that a modification in GABAB receptor expression and function may contribute to the symptoms of major depression and the response to antidepressants. This includes laboratory animal experiments demonstrating that antidepressants modify brain GABAB receptor expression and function and that GABAB receptor antagonists display antidepressant potential in animal models of this condition. Clinical and post-mortem studies reveal changes in GABAergic transmission associated with depression as well as depression-related changes in GABAB subunit expression that are localized to the cortical depression network. Detailed in this review are the preclinical and clinical data implicating a role for the GABAB receptor system in mediating symptoms of this disorder and its possible involvement in the response to antidepressants. Particular emphasis is placed on clinical and post-mortem studies, including previously unpublished work demonstrating regionally-selective modifications in GABAB receptor subunit expression in brain samples obtained from depressed subjects. Together with the earlier preclinical studies, these new data point to a role for the GABAB system in major depression and support the antidepressant potential of GABAB receptor antagonists.

 

Ginkgolide B, a constituent of Ginkgo biloba, facilitates glutamate exocytosis from rat hippocampal nerve terminals
Su-Jane Wang, Hui-Hsin Chen (2005)

Although previous studies have demonstrated that Ginkgo biloba extract has modest effects in the improvement of memory and cognitive function of the Alzheimer's disease patients, the mechanism(s) underlyling its beneficial effects remain(s) unclear. In this study, the effect of ginkgolide B, one of the major constituents of Ginkgo biloba extract, on the release of endogenous glutamate from rat hippocampal nerve terminals (synaptosomes) was studied. Ginkgolide B facilitated the Ca2+-dependent release of glutamate evoked by 4-aminopyridine in a concentration-dependent manner. The facilitatory action of ginkgolide B was not due to it increasing synaptosomal excitability because ginkgolide B did not alter the 4-aminopyridine-evoked depolarization of the synaptosomal plasma membrane potential. Rather, examination of the effect of ginkgolide B on cytosolic free Ca2+ concentration revealed that the facilitation of glutamate release could be attributed to an enhancement of presynaptic voltage-dependent Ca2+ influx. Consistent with this, the ginkgolide B-mediated facilitation of glutamate release was significantly prevented in synaptosomes pretreated with a wide spectrum blocker of N-, P-, and Q-type Ca2+ channels, ω-conotoxin MVIIC. Moreover, the facilitation produced by ginkgolide B was completely abolished by the protein kinase A inhibitor, but not by the protein kinase C inhibitor. These results suggest that ginkgolide B effects a increase in protein kinase A activation, which subsequently enhances the Ca2+ entry through voltage-dependent N- and P/Q-type Ca2+ channels to cause a increase in evoked glutamate release from rat hippocampal nerve terminals. In addition, glutamate release elicited by Ca2+ ionophore (ionomycin) was also facilitated by ginkgolide B, which suggests that ginkgolide B may have a direct effect on the secretory apparatus downstream of Ca2+ entry. These actions of ginkgolide B may provide some information regarding the beneficial effects of Ginkgo biloba in the central nervous system.

• Ginkgo has also antagonist at GABAA and 5TH1A
• Green tea has theanine, it's pro-GABA. EGCG promotes glutamate release, and GTE also "control[s] dysregulated glutamate"
• Ginseng has antagonist at GABAB [1], and this:
   

Korean Red Ginseng Extract Activates Non-NMDA Glutamate and GABAA Receptors on the Substantia Gelatinosa Neurons of the Trigeminal Subnucleus Caudalis in Mice
Hua Yin, Seon Ah Park, Soo Joung Park, and Seong Kyu Han (2011)

Korean red ginseng (KRG) is a valuable and important traditional medicine in East Asian countries and is currently used extensively for botanical products in the world. KRG has both stimulatory and inhibitory effects on the central nervous system (CNS) suggesting its complicated action mechanisms. The substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) are involved in orofacial nociceptive processing. Some studies reported that KRG has antinociceptive effects, but there are few reports of the functional studies of KRG on the SG neurons of the Vc. In this study, a whole cell patch clamp study was performed to examine the action mechanism of a KRG extract on the SG neurons of the Vc from juvenile mice. KRG induced short-lived and repeatable inward currents on all the SG neurons tested in the high chloride pipette solution. The KRG-induced inward currents were concentration dependent and were maintained in the presence of tetrodotoxin, a voltage gated Na channel blocker. The KRG-induced inward currents were suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist and/or picrotoxin, a gamma-aminobutyric acid (GABA)A receptor antagonist. However, the inward currents were not suppressed by d,l-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist. These results show that KRG has excitatory effects on the SG neurons of the Vc via the activation of non-NMDA glutamate receptor as well as an inhibitory effect by activation of the GABAA receptor, indicating the KRG has both stimulatory and inhibitory effects on the CNS. In addition, KRG may be a potential target for modulating orofacial pain processing.

[GABAergic]

any updates to this