55 replies to this topic

[Ampa-omega]

Thanks for the post scienceguy found it very helpfull, wow didn't know that the gaba receptors can downregulate from chronic taurine!

[ScienceGuy]

Thanks for the post scienceguy found it very helpfull, wow didn't know that the gaba receptors can downregulate from chronic taurine!

You're welcome

Unfortunately, yes TAURINE is confirmed as being a GABA RECEPTOR AGONIST and hence will induce receptor down-regulation with regular use; however, the gastric and intestinal ulceration risk is in itself good enough reason to avoid prolonged high dose usage.

Edited by ScienceGuy, 29 January 2012 - 12:39 PM.

[Reformed-Redan]

1000 mg of Bacopa always gets me to sleep.

[protoject]

Thanks for the post scienceguy found it very helpfull, wow didn't know that the gaba receptors can downregulate from chronic taurine!

You're welcome

Unfortunately, yes TAURINE is confirmed as being a GABA RECEPTOR AGONIST and hence will induce receptor down-regulation with regular use; however, the gastric and intestinal ulceration risk is in itself good enough reason to avoid prolonged high dose usage.

Hey dude, do you know if the same is true for Beta-alanine?? Do you know anything about beta-alanine and its relation to GABA receptors? I'm pretty sure it is related in some similar way as taurine, in that it agonizes both gaba and glycine receptors. I'm trying to find more information on that now but was wondering if you knew anything off hand to streamline my efforts lol.

[ScienceGuy]

Thanks for the post scienceguy found it very helpfull, wow didn't know that the gaba receptors can downregulate from chronic taurine!

You're welcome

Unfortunately, yes TAURINE is confirmed as being a GABA RECEPTOR AGONIST and hence will induce receptor down-regulation with regular use; however, the gastric and intestinal ulceration risk is in itself good enough reason to avoid prolonged high dose usage.

Hey dude, do you know if the same is true for Beta-alanine?? Do you know anything about beta-alanine and its relation to GABA receptors? I'm pretty sure it is related in some similar way as taurine, in that it agonizes both gaba and glycine receptors. I'm trying to find more information on that now but was wondering if you knew anything off hand to streamline my efforts lol.

Yes, it does appear that BETA-ALANINE is a GABA RECEPTOR AGONIST - see this study for example:

Neurochem Int. 2010 Oct;57(3):177-88. Epub 2010 Jun 9.

Beta-alanine as a small molecule neurotransmitter.

Tiedje KE, Stevens K, Barnes S, Weaver DF.

Source

Department of Chemistry, Dalhousie University, B3H 4J3 Halifax, Canada.

Abstract

This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.

PMID: 20540981

[BioFreak]

Thanks for the post scienceguy found it very helpfull, wow didn't know that the gaba receptors can downregulate from chronic taurine!

You're welcome

Unfortunately, yes TAURINE is confirmed as being a GABA RECEPTOR AGONIST and hence will induce receptor down-regulation with regular use; however, the gastric and intestinal ulceration risk is in itself good enough reason to avoid prolonged high dose usage.

Hey dude, do you know if the same is true for Beta-alanine?? Do you know anything about beta-alanine and its relation to GABA receptors? I'm pretty sure it is related in some similar way as taurine, in that it agonizes both gaba and glycine receptors. I'm trying to find more information on that now but was wondering if you knew anything off hand to streamline my efforts lol.

Yes, it does appear that BETA-ALANINE is a GABA RECEPTOR AGONIST - see this study for example:

Neurochem Int. 2010 Oct;57(3):177-88. Epub 2010 Jun 9.

Beta-alanine as a small molecule neurotransmitter.

Tiedje KE, Stevens K, Barnes S, Weaver DF.

Source

Department of Chemistry, Dalhousie University, B3H 4J3 Halifax, Canada.

Abstract

This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.

PMID: 20540981

Hmm. Sounds logical, but from what I know the main side effects of beta alanine in higher doages (tingling) come from its gaba related effects. If gaba receptors get downregulated by beta alanine, the those side effects should go away over time too... but I have not heard that they do. I personally don't get the tingling not even with very high dosages so I can't confirm that, but on the other side I do get the gaba related benefits, if the dosage is right (and needs to be high for me :( ). The main problem with beta alanine is that it depletes taurine. I've found only one study confirming in cell cultures that its negative effects on taurine can be avoided if the cells get access to the same amount of taurine. Thats quite a long shot though, who knows what the right ratio for beta alanine and taurine is in a whole organism. I don't know if I get sort of a placebo side effect but I've noticed that my heart gets arrhythmic if I don't make sure I get enough taurine. And here we go, long term Taurine use is bad for the stomach... So I need a replacement with less side effects.

Also, I am not sure if beta alanine does indeed downregulate gaba receptors or not. While I have been upping the dose since I started, the positive effects also increased, so basically I did not need to up the dosage to maintain a certain level of effects. I also on occation(1-2 days) did not take beta alanine after being on high dosages (we're talking 3-9g/day here), and I did not suffer from withdrawal effects. Again, this does not support the gaba receptor downregulation hypothesis for beta alanine.

So from what I know alternatives for gaba are theanine and lithium orothate (which I will try next). However theanine has been found to lower dopamine and serotonin, I am not clear on if this comes from gaba itself (since it regulates neurotransmitters in the brain) or if it is an additional effect of theanine, but I must say that those effects are not welcome to me...

So are there other options for GABA in the brain that do not downregulate gaba receptors? Lithium seems to work by inhibiting gaba reuptake, but that also should lead to downregulation of gaba receptors long term (unless gaba is eliminated fast enough by comt/MAO enzyme systems).

Basically I'm not entirely sold on gaba receptor downregulation because lithium could not work long term as well and the dosage would need to be upped too(if indeed the only mechanism of lithium on gaba is inhibition of reuptake), but I've not heard about a increase in dosage of lithium over the long term. Maybe... its something else, such as other neurotransmitters that go down when gaba goes up, or there has to be a relatively high threshold of gaba in the brain until the receptors get downregulated.
I mean same has been said about chronic l-dopa usage if I remember right, but at least part of the picture is that high dopamine levels deplete serotonin, and without serotonin, dopamine can not work as well as if both were in balance.

Anyways... For me, increasing gaba is the most exciting topic right now since it manages to free me from various behaviours that have bugged me in the past but I was unable to change. I hope there is a good way to regulate it long term without downregulating gaba receptors...

Edited by BioFreak, 30 July 2012 - 08:44 AM.

[protoject]

Hmm. Sounds logical, but from what I know the main side effects of beta alanine in higher doages (tingling) come from its gaba related effects. If gaba receptors get downregulated by beta alanine, the those side effects should go away over time too... but I have not heard that they do. I personally don't get the tingling not even with very high dosages so I can't confirm that, but on the other side I do get the gaba related benefits, if the dosage is right (and needs to be high for me :( ). The main problem with beta alanine is that it depletes taurine. I've found only one study confirming in cell cultures that its negative effects on taurine can be avoided if the cells get access to the same amount of taurine. Thats quite a long shot though, who knows what the right ratio for beta alanine and taurine is in a whole organism. I don't know if I get sort of a placebo side effect but I've noticed that my heart gets arrhythmic if I don't make sure I get enough taurine. And here we go, long term Taurine use is bad for the stomach... So I need a replacement with less side effects.

Also, I am not sure if beta alanine does indeed downregulate gaba receptors or not. While I have been upping the dose since I started, the positive effects also increased, so basically I did not need to up the dosage to maintain a certain level of effects. I also on occation(1-2 days) did not take beta alanine after being on high dosages (we're talking 3-9g/day here), and I did not suffer from withdrawal effects. Again, this does not support the gaba receptor downregulation hypothesis for beta alanine.

So from what I know alternatives for gaba are theanine and lithium orothate (which I will try next). However theanine has been found to lower dopamine and serotonin, I am not clear on if this comes from gaba itself (since it regulates neurotransmitters in the brain) or if it is an additional effect of theanine, but I must say that those effects are not welcome to me...

So are there other options for GABA in the brain that do not downregulate gaba receptors? Lithium seems to work by inhibiting gaba reuptake, but that also should lead to downregulation of gaba receptors long term (unless gaba is eliminated fast enough by comt/MAO enzyme systems).

Basically I'm not entirely sold on gaba receptor downregulation because lithium could not work long term as well and the dosage would need to be upped too(if indeed the only mechanism of lithium on gaba is inhibition of reuptake), but I've not heard about a increase in dosage of lithium over the long term. Maybe... its something else, such as other neurotransmitters that go down when gaba goes up, or there has to be a relatively high threshold of gaba in the brain until the receptors get downregulated.
I mean same has been said about chronic l-dopa usage if I remember right, but at least part of the picture is that high dopamine levels deplete serotonin, and without serotonin, dopamine can not work as well as if both were in balance.

Anyways... For me, increasing gaba is the most exciting topic right now since it manages to free me from various behaviours that have bugged me in the past but I was unable to change. I hope there is a good way to regulate it long term without downregulating gaba receptors...

Bacopa upregulates gaba receptors.
On another note, I was mentioning in another thread that OXCARBAZEPINE is good for benzo withdrawal/ anxiety [for me] and someone else chimed in that oxcarbazepine upregulates Gaba receptors in a similar way that bacopa does.. I haven't confirmed this myself with research yet though.

[gamesguru]

Bacopa only prevents gaba downregulation in epileptic mice. Scienceguy misinterpreted the study he originally referenced. We know virtually nothing about how it affects healthy mice or humans. Oxcarbazepine probably works the same way; through anti-seizure activity.

I suspect other anticonsulvants would have a similar mechanism. Seizures downregulate gaba: http://www.ncbi.nlm....pubmed/21833845. Bacopa prevents seizures: http://www.scielo.br...ipt=sci_arttext. Ergo, bacopa only ameliorates downregulation of GABA by preventing (or reducing the frequency of) seizures in seizure-susceptible people (namely, epileptics).

Verbatim from ScienceGuy's study: "Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity".

We even have some people on this board who report that bacopa worsens anxiety, and anxiety surely goes deeper than the GABA system. One thing bacopa does reliably is enhance memory, possibly through enhancing baseline population spike amplitude and potentially VDCC LTP (but probably not NMDA LTP), like valproic acid (http://www.ncbi.nlm..../pubmed/8846106). Valproic acid also was thought to abolish NMDA LTP through PKC inhibition. It is suspected that bacopa may improve memory and recall through choline modulation or antioxidant activity (not through anticonvulsant activity), but these claims are as yet unsubstantiated (http://www.ncbi.nlm....les/PMC3095476/). Probably bacopa works through a different mechanism than your run of the mill pharmaceutical anticonvulsants. LTP, GABA, and anti-convulsion are highly interrelated (http://jp.physoc.org.../518/1/109.full).


It's unproven, almost backward, science, but GABA antagonists could upregulate GABA receptor density. Certain compounds in ginkgo can do this, but their efficacy in reducing anxiety is far from proven.

CBD is gaining weight too (http://www.ncbi.nlm....pubmed/20829306). I am using it now for a few weeks, and it seems to be helpful, though not miraculous, for treating my GAD.

Edited by dasheenster, 30 July 2012 - 04:09 PM.

[protoject]

Bacopa only prevents gaba downregulation in epileptic mice.

Oh I'm sorry, my bad. It was my mistake, I didn't even verify that about the matter when I had heard it. Totally jumped the gun on that one.

[protoject]

Do you think Pregnenolone would be useful for upregulating gaba receptors? I believe it is a gaba antagonist if I'm not mistaken. I'm not sure that effect would be worth its other effects though.

[victortsoi]

I tried pregnenalone once and it felt like a steroid injection I had to have for allergies. It's serious stuff and this is coming from someone whos tried EVERYTHING, often to excess and irresponsibility. Aniracetam is both nootropic and extremely anxiolytic for me and a lot of other people. In fact, it might be so powerful you might not want to get off your ass to do anything.

[gamesguru]

It's only documented axiolytic mechanism is GABA-Aergic (http://www.sciencedi...006899399021502)...which probably means it results in down-regulation through one route or another. Pregnenolone might enhance production of certian glucocorticoids, including cortisol, which is potently anxiogenic. This is only advisable if you're grossly deficient in other byproducts or precursors of its metabolism, like estrogens or cholesterol. In the case of cholesterol, I recommend decreasing (or increasing) dietary intake/physical exercise, and partaking in dietary changes (many foods contain things that we take as supplements, like onions contain quercetin, and egg yolks contain choline, which both have a role in regulating [brain] cholesterol). If your stress is primarily cortisol-mediated (which it probably is not...remember that anxiety disorders go deeper than cortisol dysregulation), phosphatidylserine may blunt the cortisol response from physical and mental stress (http://www.springerl...8r3551t2235342/ & http://informahealth...890410001728379), but I fear tolerance might develop after a few months, thus restoring baseline homeostasis. Similarly, if cortisol is the main casue, or a large contributing factor, supplements to boost BDNF function will help unless down-regulation develops, since stress reduces BDNF expression. Check out the "neurotophic factor" thread for lists. I recommend curcuminoids and low-doses of korean ginseng. Currently on day 12 of curcumin supplementation, 3-4x daily of 50 mg curcuminoids...and I'm debating whether or not I can tell if tolerance is setting in. Probably if I notice initial clues indicative of tolerance, I'll cut it out for at least 5-7 days.

The mechanisms through which aniracetam and piracetam exert their purported anxiolytic properties have, as yet, to the best of my knowledge, not been clearly isolated or delineated by scientific research. I'd be interested to hear speculations on this, as I'm drawing a blank and have nothing to say off the top of my head. One study implicates that piracetam inhibits serotonin metabolism and turnover (http://www.ncbi.nlm....ov/pubmed/95599). Very bewildering.

Other compounds I have not yet lost faith in include cannabidiol, adafenoxate, gotu kola/ashwagandha (I don't think their only anxiolytic mechanism is GABAergic, though I cannot prove this). I'm learning that it's important to have yoga/meditation/quiet time (at the least). It's also important to have good people around you, as well as a few bad ones (we all have anger, as I believe it, and to suppress this to an unnatural extent only causes instability). You can try benzos or alcohol, or THC, but these all have rebound effects, like any potent GABAergic. Personally, I don't even use these occasionally, because I believe they're basically patchjobs. I'm really liking cannabidiol, but it has some negative effects, and I'm currently debating whether or not they counterbalance and dominate the positive effects.

Edited by dasheenster, 01 August 2012 - 01:47 AM.

[ScienceGuy]

Bacopa only prevents gaba downregulation in epileptic mice. Scienceguy misinterpreted the study he originally referenced. We know virtually nothing about how it affects healthy mice or humans...

Bacopa only prevents gaba downregulation in epileptic mice.

Oh I'm sorry, my bad. It was my mistake, I didn't even verify that about the matter when I had heard it. Totally jumped the gun on that one.

Firstly, sorry for the delay in getting around to replying, I have been crazily busy and for a variety of reasons was absent from this forum for a number of months.

In short, dasheenster yes you are quite correct that that singular study you have cherry picked is a RODENT STUDY (its RATS by the way, not MICE to be entirely accurate) wherein the RATS are indeed EPILEPTIC; however, you are guilty of 'throwing the baby out with the bathwater' by making such a dismissive sweeping statement as "Bacopa only prevents gaba downregulation in epileptic mice", since this is not in fact the only study that is indicative that BACOPA MONNIERI exerts a POSITIVE effect on the GABAergic SYSTEM.

See this other study for example, which I also quoted along with the other one, which in indicative that BACOPA MONNIERI reverses the effects of Diazepam on the benzodiazepine pathway and possibly potentiates it:

Psychopharmacology (Berl) 2008 Sep;200(1):27-37. Epub 2008 Jan 13.
Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice.

Prabhakar S, Saraf MK, Pandhi P, Anand A.
Source

Department of Neurology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India.
Abstract

RATIONALE:

As Benzodiazepines are known to produce amnesia by involvement of the GABAergic system, we examined Bacopa monniera, an herb known for memory enhancement for reversal of memory deficits caused by diazepam.
OBJECTIVES:

The objective of the study was to study the effect of standardized extract of B. monniera on diazepam-induced amnesia in mice using Morris water maze.
MATERIALS AND METHODS:

We used the rota rod test as a screening measure for muscle incoordination followed by the Morris water maze scale to evaluate the effect of B. monniera on amnesia. The index of acquisition and retrieval was recorded with varying doses of Bacopa.
RESULTS:

The results revealed antiamnesic effects of B. monniera (120 mg kg(-1) oral) on diazepam (1.75 mg kg(-1) intraperitoneal)-induced amnesia. The degree of reversal by Bacopa was significant as it progressively reduced escape latency time when mice treated with diazepam were subjected to acquisition trials.
CONCLUSIONS:

The antiamnesic effects of Bacopa suggest likely a gamma-aminobutyric acid-benzodiazepine pathway possibly affecting long-term potentiation.

PMID: 18193203

-------------------------------------------------------------------------------------------------------------------------------------------

And here's another study for example that further supports BACOPA's ANXIOLYTIC effect:

Indian J Exp Biol. 2010 Mar;48(3):306-13

Comparative evaluation of Bacopa monniera and Panax quniquefolium in experimental anxiety and depressive models in mice

Chatterjee M; Verma P; Palit G

Source

Division of Pharmacology, Central Drug Research Institute, CSIR, Lucknow 226 001, India

EXTRACT FROM FULL TEXT:

The light dark test has been widely used for modeling anxiety, and it has been developed for predicting the efficacy of clinically used compounds for treating this disease. Administration of BM [Bacopa Monnieri] at the dose on 80mg/kg produced a significant response in the light/dark test of anxiety… indicating and anxiolytic activity of the extract… BM [Bacopa Monnieri] demonstrated significant anxiolytic and antidepressant potential…

The anxiolytic and antidepressant effect of both PQ [Panax quniquefolium] and BM [Bacopa Monnieri] at the same dose may be beneficial as therapy for cases of mixed anxiety and depressive disorders. Thus our results fortify the ethnopharmacological importance of BM [Bacopa Monnieri] and PQ [Panax quniquefolium]in psychiatric disorders like anxiety, depression and Mixed Anxiety-Depression Disorder (MADD)…

-------------------------------------------------------------------------------------------------------------------------------------------

It is important to take note of ALL the studies and not just the one

Even so, I wholeheartedly agree that more research is needed; since despite there existing multiple studies there exists a pitiful quantity conducted on HUMANS

Edited by ScienceGuy, 12 September 2012 - 06:44 PM.

[nupi]

This is purely anecdotal conjecture, but after trying Escitalopram for a week (incidentally because of Science Guy's comments on it, I would have preferred a MAOB-I but doctor would not go for it, so I figured lets try the most specific SSRI first), I am wondering if Bacopa is not more of a serotonergic than GABAergic (even if its upregulating GABA). Bacopa initially felt very much like what I now start to feel from Escitalopram (minus the annoying headache) and never much like what typical GABAergic would do (think benzo or even booze). I guess it would also explain why Bacopa lowers libido as SSRIs are notorious for all kinds of sexual side effects...

One thing I wonder now is whether one could stack Escitalopram and Bacopa without risking Serotonin Toxicity (I've gotten rid of Rhodiola for obvious reasons)...

Edited by nupi, 13 September 2012 - 06:33 AM.

[ScienceGuy]

This is purely anecdotal conjecture, but after trying Escitalopram for a week (incidentally because of Science Guy's comments on it, I would have preferred a MAOB-I but doctor would not go for it, so I figured lets try the most specific SSRI first), I am wondering if Bacopa is not more of a serotonergic than GABAergic (even if its upregulating GABA). Bacopa initially felt very much like what I now start to feel from Escitalopram (minus the annoying headache) and never much like what typical GABAergic would do (think benzo or even booze). I guess it would also explain why Bacopa lowers libido as SSRIs are notorious for all kinds of sexual side effects...

One thing I wonder now is whether one could stack Escitalopram and Bacopa without risking Serotonin Toxicity (I've gotten rid of Rhodiola for obvious reasons)...

The science indicates that not unsurprisingly BACOPA MONNIERI's mechanism of action is via more than one pathway, specifically it is possible that it positively potentiates the GABAergic pathway; as well as acting as an ADAPTOGEN, and thereby positively influencing the stress response; and have an effect on the SEROTONIN system too. An influence on the SEROTONIN system would certainly explain BACOPA's reported ANTIDEPRESSANT effect

However, through what precise mechanism of action BACOPA induces its reported ANTIDEPRESSANT effect is not yet explained by substantiated scientific evidence since there currently exists conflicting information... see here for example:

1. J Ethnopharmacol. 2011 Mar 8;134(1):55-61. Epub 2010 Dec 1.

Bacopa monniera leaf extract up-regulates tryptophan hydroxylase (TPH2) and
serotonin transporter (SERT) expression: implications in memory formation.

Charles PD, Ambigapathy G, Geraldine P, Akbarsha MA, Rajan KE

Source
Department of Animal Science, School of Life Sciences, Bharathidasan University,
Palkalaiperur, Tiruchirappalli 620024, Tamil Nadu, India.

Abstract
AIM OF THE STUDY: To examine the effect of Bacopa monniera leaf ethanolic extract
(BMEE) on the serotonergic system of postnatal rats with reference to learning
and memory.

MATERIALS AND METHODS: From postnatal day (PND)-15-29, rats were treated with
BMEE (40 mg/kg BW+0.5% gum acacia) by oral gavage. Behavioural tests (Y-maze,
hole-board and passive avoidance) were used to evaluate their learning
(PND-32-37) and retention of memory (PND-47-53). Effect of BMEE on
neurotransmitter system was analyzed by ELISA and semi-quantitative polymerase
chain reaction (PCR).

RESULTS: Oral administration of BMEE improved learning and retention of memory
significantly in all behavioural tasks. Following BMEE treatment, the level of
serotonin (5-HT) increased while dopamine (DA) decreased significantly. We also
found variation in the level of acetylcholine (ACh). However, no significant
changes were observed in the level of ACh and glutamate (Glu). The level of 5-HT
was significantly elevated up to PND-37 and was then restored to normal level on
PND-53. Interestingly, concomitant up-regulation was recorded in the mRNA
expression of serotonin synthesizing enzyme tryptophan hydroxylase-2 (TPH2) and
serotonin transporter (SERT) on PND-29 and PND-37, which was restored on PND-53.

CONCLUSIONS: The results suggest that BMEE treatment significantly enhances the
learning and retention of memory in postnatal rats possibly through regulating
the expression of TPH2, 5-HT metabolism and transport.

----------------------------------------------------------------------------------------------------------------------------------------

Phytother Res. 2012 May;26(5):758-63. doi: 10.1002/ptr.3631. Epub 2011 Nov 22.

A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity
plus the elevated striatal dopamine and serotonin turnover.

Rauf K, Subhan F, Sewell RD.

Source
Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.

Abstract
Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic,
anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant
(nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3,
Bacopaside II and Bacopasaponin C). The effects of the BM extract were then
studied on morphine-induced hyperactivity as well as dopamine and serotonin
turnover in the striatum since these parameters have a role in opioid sensitivity
and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15
mg/kg, orally), 60 min before morphine administration and locomotor activity was
subsequently recorded. Immediately after testing, striatal tissues were analysed
for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with
electrochemical detection. The results indicated that nBt-ext BM significantly (p
< 0.001) decreased locomotor activity in both the saline and morphine treated
groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine
(DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and
5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to
affect DA, 5-HT and their metabolites in the saline treated group. These findings
suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have
potential beneficial effects in the treatment of morphine dependence.

Edited by ScienceGuy, 13 September 2012 - 07:43 AM.

[ScienceGuy]

This is purely anecdotal conjecture, but after trying Escitalopram for a week...

Please kindly note that, for a variety of reasons, I do not recommend ESCITALOPRAM as the first treatment option for treating DEPRESSION and/or ANXIETY disorders.

For certain instances it is suggested that individuals try taking ESCITALOPRAM at no a dosage of no greater than 5mg OD; however, this is only in certain circumstances when other treatment options have been exhausted and/or unusual particular requirements are applicable (such as an instance wherein someone specifically sought to positive modulate SEROTONIN wherein ESCITALOPRAM at 5mg OD dosage was the best choice versus the alternative being proposed, namely taking high doses of L-5HTP for prolonged periods, which is ill-advised due to associated increase in CARDIOVASCULAR DISEASE).

For those taking ESCITALOPRAM I recommend limiting the dosage to 5mg OD which has been shown to be therapeutic whilst minimising the potential for SSRI associated SIDE EFFECTS; and further to this I recommend that INOSITOL be taken in combination to help prevent / offset any ESCITALOPRAM induced DOWNREGULATION of the SEROTONIN RECEPTORS. N.B. Studies have shown that INOSITOL taken in combination with ESCITLOPRAM does not yield any superior ANTIDEPRESSANT effect, however what it does do is UPREGULATE / RE-SENSITIZE the SEROTONIN RECEPTORS

One thing I wonder now is whether one could stack Escitalopram and Bacopa without risking Serotonin Toxicity (I've gotten rid of Rhodiola for obvious reasons)...

What dosage of ESCITALOPRAM are you taking? If you are only taking 5mg OD then manifestation of SEROTONIN SYNDROME is highly unlikely if stacked with BACOPA, even if it does somewhat increase SEROTONIN LEVELS, wherein there exists inconclusive / conflicting scientific evidence... think of it this way, ESCITALOPRAM at 5mg OD DOSAGE taking in combination with BACOPA almost certainly will not elevate SEROTONIN LEVELS as much as the 'standard' prescribed dosage of 20mg ESCITALOPRAM, and as such one can deduce would not be capable of inducing SEROTONIN SYNDROME

Edited by ScienceGuy, 13 September 2012 - 08:24 AM.

[nupi]

So what are you recommending as first line treatment? I have tried some of the more obvious choices
1) Fish oil: subjectively did nothing, but I still take it
2) Magnesium: if anything, very limited impact
3) Bacopa: works, but makes me too tired during day time
4) Effexor (a decade ago): worked, but the side effect profile is inacceptable
5) Wellbutrin: gives energy, does nothing for anxiety (if does not actually exacerbate it)

I would have loved to try Selegiline or Rasagiline but the doc would not go for it... As for dosage, I started on 5mg (was prescribed 10 but I never cared much for dosage advice from docs) and probably should try 5mg for another week or two to see if it is strong enough.

Good point on the Inositol, I might try that (never did much for me stand alone)

[ScienceGuy]

So what are you recommending as first line treatment?

That depends upon what is precisely being treated

Are you seeking to treat ANXIETY or DEPRESSION or BOTH?

Further to this, if ANXIETY, have you been specifically diagnosed as suffering from an ANXIETY DISORDER? If so, what exactly? (as differing first line treatment for different disorders)

I have tried some of the more obvious choices
1) Fish oil: subjectively did nothing, but I still take it

Just bear in mind that FISH OIL can have opposing effects, differing from person to personl; wherein it can improve or worsen ANXIETY and/or DEPRESSION

2) Magnesium: if anything, very limited impact

IMO never a 'magic bullet' but often a useful adjunct, providing a helpful mild ANXIOLYTIC effect through NMDA RECEPTOR ANTAGONISM that can be stacked with other ANXIOLYTICS that have other mechanisms of action wherein the combination yields the desired overall effect

3) Bacopa: works, but makes me too tired during day time

Have you tried taking the BACOPA as a single dose at bedtime? For some people (but not others) this minimises the BACOPA induced daytime fatigue

I would have loved to try Selegiline or Rasagiline but the doc would not go for it...

You can actually obtain SELEGILINE via the Internet without a prescription; however, you should be aware that a common side effect is in fact ANXIETY, and hence there is a significant probability that it might exacerbate a pre-existing ANXIETY DISORDER; and the same goes for RASAGILINE

As for dosage, I started on 5mg (was prescribed 10 but I never cared much for dosage advice from docs) and probably should try 5mg for another week or two to see if it is strong enough.

I would strongly advise that you do not increase the ESCITALOPRAM dosage above 5mg unless absolutely necessary. It is all about RISK versus REWARD; and in the case of ESCITALOPRAM the RISK versus REWARD ratio when it is taken at the 5mg OD dosage (only) is such that in certain circumstances it is the right choice for treating certain types of ANXIETY and/or DEPRESSION DISORDERS; however, it should be noted that the RISK escalates exponentially as the dosage is increased and subsequently the manifestation of undersirable and classic SSRI-associated SIDE EFFECTS becomes more probable.

My advice would be to see how you get on with the ESCITALOPRAM at the 5mg dosage; and if you find it provides you with more POSITIVES than NEGATIVES stick with it at that dosage; and if you find that the POSITIVE effects are not 'strong enough' then you should go down the route of adding other complimentary ANXIOLYTICS in combination with the ESCITALOPRAM as opposed to increasing its dosage

Good point on the Inositol, I might try that (never did much for me stand alone)

Just watch for GASTROINTESTINAL SIDE EFFECTS; and note that these are typically DOSAGE DEPENDANT

Edited by ScienceGuy, 13 September 2012 - 09:30 AM.

[nupi]

As for diagnoses, I have decided to skip the PsyDoc this time round - takes a lot of time and ultimately just confirms whatever diagnosis I convince him I have anyway. But my GP was definitely worried I was close to a burn out (I initially went to him because even though I was on holiday, I couldnt sleep which has previously never happened), manifesting in the below two broad areas:

Depression:
I do not fully qualify for MDD (I had MDD a decade ago and this is very different) but definitely fullfil the criteria for Dysthimia. In particular, lack of motivation, negative outlook on life, anhedonia and fatigue that cannot be explained physiologically.

Anxiety: I have a tendency to ruminate about the future (well knowing that my thoughts are largely irrational) which takes a lot of energy and very often results in sleep maintenance insomnia. Additionally, I have an extremely stressful job (thinking of switching careers though) which fuels anxiety to some degree... All in all, it's partly social anxiety, partly generalized but not to a crippling level (but definitely above what is sustainable for the long term). Thankfully, I don't have any panic attacks.

Somewhere between the two I am also quite avoidant (or maybe at the root of it all), trying to stay away from all situations that could somehow result in "failure" (or what my mind would code as one)

Have you tried taking the BACOPA as a single dose at bedtime? For some people (but not others) this minimises the BACOPA induced daytime fatigue

That deals with the anxiety for a while but sadly not for much longer than a few hours in the morning of the next day, so ultimately not all that helpful. Ashwaghanda is better when it comes to daytime fatigue but I don't want to take a gabaergic over the long time. I also tried Rhodiola (in the morning), for a while it seemed to work quite well (definitely providing mood uplift) but stopped doing much at all after three or four weeks.

Edited by nupi, 13 September 2012 - 11:44 AM.

[hadora]

Bacopa only prevents gaba downregulation in epileptic mice. Scienceguy misinterpreted the study he originally referenced. We know virtually nothing about how it affects healthy mice or humans. Oxcarbazepine probably works the same way; through anti-seizure activity.

I suspect other anticonsulvants would have a similar mechanism. Seizures downregulate gaba: http://www.ncbi.nlm....pubmed/21833845. Bacopa prevents seizures: http://www.scielo.br...ipt=sci_arttext. Ergo, bacopa only ameliorates downregulation of GABA by preventing (or reducing the frequency of) seizures in seizure-susceptible people (namely, epileptics).

Verbatim from ScienceGuy's study: "Treatment with B. monnieri and bacoside A prevents the occurrence of seizures thereby reducing the impairment of GABAergic activity".

We even have some people on this board who report that bacopa worsens anxiety, and anxiety surely goes deeper than the GABA system. One thing bacopa does reliably is enhance memory, possibly through enhancing baseline population spike amplitude and potentially VDCC LTP (but probably not NMDA LTP), like valproic acid (http://www.ncbi.nlm..../pubmed/8846106). Valproic acid also was thought to abolish NMDA LTP through PKC inhibition. It is suspected that bacopa may improve memory and recall through choline modulation or antioxidant activity (not through anticonvulsant activity), but these claims are as yet unsubstantiated (http://www.ncbi.nlm....les/PMC3095476/). Probably bacopa works through a different mechanism than your run of the mill pharmaceutical anticonvulsants. LTP, GABA, and anti-convulsion are highly interrelated (http://jp.physoc.org.../518/1/109.full).


It's unproven, almost backward, science, but GABA antagonists could upregulate GABA receptor density. Certain compounds in ginkgo can do this, but their efficacy in reducing anxiety is far from proven.

CBD is gaining weight too (http://www.ncbi.nlm....pubmed/20829306). I am using it now for a few weeks, and it seems to be helpful, though not miraculous, for treating my GAD.

where did you get it if you don't mind me asking ?
how much are you taking and what are the side ? if any
thanks

[jetmango]

it seems taurine is a GABA agonist, so down regulation is possible with 'chronic' use now... what is 'chronic' use? 1 500mg tablet per day for 2 months , or what? ; )

[KimberCT]

Taurine

&alpha;&beta; receptor - agonist
&alpha;&beta;&gamma; receptor - partial agonist
&alpha;&beta;&delta; receptor - super agonist

From my reading, &alpha;&beta; GABA subunits are benzodiazepine insensitive, &alpha;&beta;&gamma; receptors are modulated by benzodiazepines, and &alpha;&beta;&delta; receptors are extrasynaptic neurosteroid receptors.

http://www.ncbi.nlm....?report=classic

[sensei]

Beta alanine is a component of l-carnosine , most evidence points to the main miss of action being GABA reuptake inhibition

[sensei]

Duplicate sorry

Edited by sensei, 01 May 2015 - 02:28 PM.

[sensei]

Taurine actually changes the concentrations of both glutamate and GABA by acting on the precursors glutamine and alanine.

The finding that taurine binds to GABA receptors in the thalamus of rats, does not prove agonist. It could be a Pam, antagonist, inverse agonist, or act as a necessary cOmolecule

[jetmango]

good stuff

Edited by mangoa, 02 May 2015 - 04:24 PM.