72 replies to this topic

[gizmobrain]

 

http://www.ncbi.nlm....pubmed/25259918

 

Cell. 2014 Sep 25;159(1):33-45. doi: 10.1016/j.cell.2014.07.051.

Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.

Agudelo LZ1, Femenía T2, Orhan F3, Porsmyr-Palmertz M1, Goiny M3, Martinez-Redondo V1, Correia JC1, Izadi M1, Bhat M4, Schuppe-Koistinen I4, Pettersson AT1, Ferreira DM1, Krook A5, Barres R5, Zierath JR6, Erhardt S3, Lindskog M7, Ruas JL8.

Author information

Abstract

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

 

 

This seems to be the most easily obtainable strategy for reducing kynurenine in the brain without possible side effects. Can anyone find any ways to enhance PGC-1α1-PPARα/δ pathway activation? 

 

 

I was looking for non-exotic solutions, and stumbled upon electroacupuncture... 

 

 

Med Sci Monit. 2015 Nov 4;21:3356-62.

Electroacupuncture Upregulates SIRT1-Dependent PGC-1α Expression in SAMP8 Mice.

Dong W1, Quo W2, Wang F1, Li C1, Xie Y1, Zheng X1, Shi H1.

Author information

 

Abstract

BACKGROUND Abnormalities of brain energy metabolism are involved in Alzheimer disease (AD). Sirtuin 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), which enhances mitochondrial biogenesis and energy homeostasis. Electroacupuncture (EA) has been reported to improve brain energy metabolism in AD. However, the effect of EA on SIRT1 and PGC-1α in AD remains unclear. MATERIAL AND METHODS ATP levels were measured using assay kits in the hippocampus and frontal cortex of senescence-accelerated mouse prone 8 (SAMP8) mice. Western blotting analysis and quantitative real-time RT-PCR were performed to measure the expression of SIRT1 and PGC-1a in the hippocampus of SAMP8 mice. PGC-1α acetylation was analyzed using immunoprecipitation. RESULTS Compared with senescence-accelerated resistant mice 1 (SAMR1) mice, SAMP8 mice had a decline in ATP levels and the expression of SIRT1 and PGC-1α. EA treatment improved ATP levels, upregulated the expression of SIRT1 and PGC-1α, and decreased PGC-1α acetylation. CONCLUSIONS These data suggest that EA improved brain energy metabolism, potentially associated with the upregulation of SIRT1-dependent PGC-1α expression.

 

 

 

But also, 

 

 

J Strength Cond Res. 2015 Aug 28. [Epub ahead of print]

ACUTE RESPONSE OF PGC-1α AND IGF-1 ISOFORMS TO MAXIMAL ECCENTRIC EXERCISE IN SKELETAL MUSCLE OF POSTMENOPAUSAL WOMEN.

Dieli-Conwright CM1, Kiwata JL, Tuzon C, Spektor TM, Sattler FR, Rice JC, Schroeder ET.

Author information

 

Abstract

PGC-1α4, a novel isoform of the transcriptional coactivator PGC-1α, was recently postulated to modulate the expression of anabolic and catabolic genes and therefore regulate skeletal muscle hypertrophy. Resting levels of PGC-1α4 mRNA expression were found to increase in healthy adults after resistance training. However, the acute effect of resistance exercise (RE) on PGC-1α4 expression in populations prone to progressive muscle loss, such as postmenopausal women, has not been evaluated. Here we investigated alterations in mRNA expression of PGC-1α4 and PGC-1α1, a regulator of muscle oxidative changes, in postmenopausal women following high-intensity eccentric RE, and analyzed these findings with respect to changes in IGF-1 and catabolic gene expression. Nine postmenopausal women (57.9 ± 3.2 yr) performed 10 sets of 10 maximal eccentric repetitions of single-leg extension with 20 second rest periods between sets. Muscle biopsies were obtained from the vastus lateralis of the exercised leg before and 4 hours after the RE bout with mRNA expression determined by qRT-PCR. No significant changes in the mRNA expression of either PGC-1α isoform were observed following acute eccentric RE (P > 0.05). IGF-1Ea mRNA expression significantly increased (P < 0.05) while IGF-1Eb and MGF did not significantly change (P > 0.05). PGC-1α4 mRNA expression was associated with reduced mRNA expression of the catabolic gene myostatin (R = -.88, P < 0.01), while MGF mRNA expression was associated with reduced mRNA expression of the catabolic gene FOXO3A (R = -.81, P < 0.05). These data demonstrate an attenuated response of PGC-1α isoforms to an acute bout of maximal eccentric exercise with short rest periods in postmenopausal women.

 

So if the same holds true of other age/gender groups, then maximal eccentric exercise with short rest periods... My guess is HIIT or SMIT with eccentric exercises would not only help with this, but also have numerous other benefits.

[lostfalco]

 

This seems to be the most easily obtainable strategy for reducing kynurenine in the brain without possible side effects. Can anyone find any ways to enhance PGC-1α1-PPARα/δ pathway activation? 

 

So if the same holds true of other age/gender groups, then maximal eccentric exercise with short rest periods... My guess is HIIT or SMIT with eccentric exercises would not only help with this, but also have numerous other benefits.

 

Yep, exercise would be #1 for pgc-1a. 

 

I really like PQQ as well. 

 

My friend Joe Cohen has compiled a nice list of ways to increase pgc-1a. http://selfhacked.co...Increase_PGC-1a

Edited by lostfalco, 09 November 2015 - 12:56 AM.

[lostfalco]

Another way to enhance pgc-1a is through feeding your microbiome which causes it to produce short chain fatty acids (acetate, propionate, butyrate, etc.). 

 

"The main products of intestinal bacterial fermentation of dietary fiber are short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate [8]."

 

"Butyrate enhances fatty acid oxidation and thermogenesis by increasing the expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and the phosphorylation of adenosine-monophosphate-activated kinase (AMPK) in muscle and liver tissues, and the expression of PGC-1α and mitochondrial uncoupling protein-1 (UCP-1) in brown adipose tissues [21]."

 

http://www.ncbi.nlm....les/PMC4425176/

 

Nutrients. 2015 Apr 14;7(4):2839-49. doi: 10.3390/nu7042839.

Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation.

Kasubuchi M1, Hasegawa S2, Hiramatsu T3, Ichimura A4, Kimura I5,4.

Author information

Abstract

During feeding, the gut microbiota contributes to the host energy acquisition and metabolic regulation thereby influencing the development of metabolic disorders such as obesity and diabetes. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. In this review, we summarize the roles of gut microbial SCFAs in the host energy regulation and present an overview of the current understanding of its physiological functions.

 

[sativa]

This thread caught my eye because of the mention of norharman (a beta-carboline) and sarcosine. Both 9-methyl-beta-carboline and sarcosine have a positive impact on my issues with low motivation, so I will be attempting to digest the information about the pathways mentioned to see if it might apply to me.

Re low motivation, have you tried Manganese - it's involved (along with Magnesium) in dopamine synthesis.

Also, high prolactin causes low dopamine (they have an inverse relationship).

Low testosterone could also be a factor at play.

Chaste berry fixes both of these potential issues as it is a D2 agonist (so lowers prolactin) and (from what I gather from this forum) in males, it increases testosterone.

It might seem like an odd suggestion, but ylang ylang essential oil could be of use to you regarding general motivation. Also, Mandarin and tea tree oils both activate the D1 receptor.

Finally Orexin. A very interesting substance. It promotes wakefulness.

Detailed information can be found here:
selfhacked.com/2014/02/12/how-to-increase-orexin-and-decrease-fatigue-naturally/


Also, could you please provide any insight you gain from studying the KYN pathway that would he relevant to increasing KYN acid for its antagonist properties?

[sativa]

In particular, indoles in cruciferous veggies are very important for gut health. Indoles shift the metabolism of trypotophan to serotonin, instead of kynurenine.

http://selfhacked.co...s-sulforaphane/

Indolamine dioxygenase (IDO) is the key enzyme involved in the conversion of tryptophan in the intestine. The enzyme catalyses oxidation of tryptophan to kynurenine in a reaction that produces peroxide and gives rise to highly reactive and potentially harmful oxygen and hydroxyl radicals.

http://www.ncbi.nlm....les/PMC4266036/

Edited by sativa, 13 November 2015 - 11:04 AM.

[gizmobrain]

I have tried numerous nootropics/supplements/etc in the past few years to get away from internal distraction, anticipatory anhedonia, bouts of insomnia, low energy, and above all else, extremely low motivation. I've found things that help, but looking for a root cause (and potentially the healthiest 'fix') always keeps me coming back for more knowledge.

I've been trying to decipher how to tip the scale against KYNA metabolism in the brain by breaking down the pathway and looking for things that might be of help that I already have in my medicine cabinet in order to test if my hypothesis is correct (i.e. that too much brain KYNA during the day might be the source of my issues). 3 days this week, I had interesting results with some of the least exotic supplements yet. Below, the red bolded items are what I have added this week (ceasing consumption of all additional items that I usually rotate for my low motivation/focus symptoms):

8AM - Empty Stomach

• 3 caps Jarrow's N-Actyl-L-Tyrosine (~1g)
• 1 cap Now L-Theanine (100mg)
• 1 cap BrickerLabs OptiFlow (30mg of ResVida Resveratrol + 150mg FruitFlow)
• 1 cap Vibrant Health Super Natural Boron (3mg Boron from CFB, 338mg Broccoli powder)

9AM - With Scrambled Eggs

• 1 cup coffee
• 1 cap Jarrow's Bone-Up (Vit C/D3/MK-7/Calcium/Zinc/Magnesium/Manganese/Boron)
• 1 tsp Carlson's Fish Oil (~1.6g Omega 3)
• 5000IU Doctor's Best Vitamin D3

10:15AM - Empty Stomach

• 1 tsp Chocomine (~5g)
• 1 tsp BCAA (2.5g of L-Leucine, 1.25g of IsoLeucine, 1.25g of L-Valine)
• 1 tsp Creatine (~5g)

10:45AM - 11:45AM

• Weight Lift at Gym

12PM

• Salad with Chicken, olive oil, hot sauce, veggies

Afternoon

• Neuro Sonic (energy drink that has a bit of caffeine, l-theanine, Alpha GPC and phosphatidylserine)
• Jasmine Tea

Dinner

• 1 cap Jarrow's Bone-Up (Vit C/D3/MK-7/Calcium/Zinc/Magnesium/Manganese/Boron)

Evening

• 1 sachet Bimuno in roobios tea

By far the most shocking impact is that 1g of NALT has been effective at wiping out the sleepiness on my morning drive to work before coffee, and boosting motivation, energy, and mood for what seems to be most of the day (though it could be prolonged by the other substances for sure). I generally take 200mg of NALT merely for maintenance purposes, having taken up to 500mg in one dose before without much of a noticeable effect. I've also taken 350mg twice a day without any effects. Apparently some magic happens around the 1 gram dosage level for me. With a dose that high of an n-acetyl version, I worry about possible side effects of daily usage, so I definitely need to elucidate why this is working and how optimize it.

Also, I normally require melatonin to sleep, but the 3 days I've taken this, I have essentially "passed out" around 11PM (barely remember getting in bed) and have slept very soundly.

Motivation, energy, and mood have all been fairly substantially raised from my usual baseline. Not as high as my 5mg forskolin/2mg D-Amp ER/500mg Artichoke extract stack, but that's always an unnaturally high level of motivation. I know most folks would look at this and say "you got that dopamine deficiency, bro" but I've taken plenty of different dopaminergics before without this kind of well-balanced result.

I've got a ton of information running around in my brain about my genetics (have some interesting stuff going on in the TPH genes), about the TRP/KYNA pathway, and how it might relate to my experiences with different supplements/herbs/pharmaceuticals. I don't know yet if it all adds up, because my understanding is small (but growing). Hopefully I'll be able to organize some of the connections I may be making.
 
TL;DR Least exciting supplement stack... works suspiciously well, and I think it mostly comes down to the addition of 1g of NALT in the morning. Might be because of its impact on KYNA formation or maybe just because it's a dopamine precursor.

[lostfalco]

I've been trying to decipher how to tip the scale against KYNA metabolism in the brain by breaking down the pathway and looking for things that might be of help that I already have in my medicine cabinet in order to test if my hypothesis is correct (i.e. that too much brain KYNA during the day might be the source of my issues). 

Hey gizmodroid, have you tried galantamine?

 

There are more studies if you're interested but I'll just link one for now. =)

 

http://www.ncbi.nlm....les/PMC3622758/

 

Neuroscience. 2013 May 15;238:19-28. doi: 10.1016/j.neuroscience.2013.01.063. Epub 2013 Feb 6.

Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: reversal with galantamine.

Alexander KS1, Pocivavsek A, Wu HQ, Pershing ML, Schwarcz R, Bruno JP.

Author information

Abstract

Levels of kynurenic acid (KYNA), an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, are elevated in the brain of patients with schizophrenia (SZ) and might contribute to the pathophysiology and cognitive deficits seen in the disorder. As developmental vulnerabilities contribute to the etiology of SZ, we determined, in rats, the effects of perinatal increases in KYNA on brain chemistry and cognitive flexibility. KYNA's bioprecursor l-kynurenine (100mg/day) was fed to dams from gestational day 15 to postnatal day 21 (PD21). Offspring were then given regular chow until adulthood. Control rats received unadulterated mash. Brain tissue levels of KYNA were measured at PD2 and PD21, and extracellular levels of KYNA and glutamate were determined by microdialysis in the prefrontal cortex in adulthood (PD56-80). In other adult rats, the effects of perinatal l-kynurenine administration on cognitive flexibility were assessed using an attentional set-shifting task. l-Kynurenine treatment raised forebrain KYNA levels ∼3-fold at PD2 and ∼2.5-fold at PD21. At PD56-80, extracellular prefrontal KYNA levels were moderately but significantly elevated (+12%), whereas extracellular glutamate levels were not different from controls. Set-shifting was selectively impaired by perinatal exposure to l-kynurenine, as treated rats acquired the discrimination and intra-dimensional shift at the same rate as controls, yet exhibited marked deficits in the initial reversal and extra-dimensional shift. Acute administration of the α7nAChR-positive modulator galantamine (3.0mg/kg, i.p.) restored performance to control levels. These results validate early developmental exposure to l-kynurenine as a novel, naturalistic animal model for studying cognitive deficits in SZ.

 

 

 

[gizmobrain]

Hey gizmodroid, have you tried galantamine?

There are more studies if you're interested but I'll just link one for now. =)

 

http://www.ncbi.nlm....les/PMC3622758/

 

Yes, I sure have. Also GTS-21. Both seem to have a positive impact on peeling back the brain fog! Unfortunately, they seem to do absolutely nothing for motivation, which is the big one. 

 

That's why this pathway has me very interested. I find nAChR agonists to be useful for undoing the brain fog, and glutamatergic related substances to be useful for motivation. Since KYNA antagonizes both receptor types, I figure that its possible that I have too much of it during the day (or possibly not enough at night for upregulation?).

Edited by gizmodroid, 15 November 2015 - 02:06 AM.

[lostfalco]

 

 

 

Yes, I sure have. Also GTS-21. Both seem to have a positive impact on peeling back the brain fog! Unfortunately, they seem to do absolutely nothing for motivation, which is the big one. 

 

That's why this pathway has me very interested. I find nAChR agonists to be useful for undoing the brain fog, and glutamatergic related substances to be useful for motivation. Since KYNA antagonizes both receptor types, I figure that its possible that I have too much of it during the day (or possibly not enough at night for upregulation?).

 

Got it. Cool. I hope you find something that works for motivation as well!

[gizmobrain]

 

 

Got it. Cool. I hope you find something that works for motivation as well!

 

Fasoracetam seems to do really well for everything except not quite enough on the motivation side of things. Nefiracetam is excellent for my cognition and motivation, but there has always been concerns about daily use. Panax Ginseng is great for motivation but induces anger (I call it 'the rage pill'), and doesn't seem to do much for cognition. Selegiline never seemed to do much of anything unless combine with other stuff. 

 

By far the biggest success I've ever had is a modified CILTEP stack that I've taken for the majority of the last 3 years (5mg forskolin/500mg Artichoke Extract/2mg D-Amphetamine ER).

[gizmobrain]

Years ago, I researched why NSAID's seem to give me a mood boost... at the time I didn't find much. Oddly, I have been able to find quite a bit of info this time around:
 

 

 

COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence.

Abstract

Antidepressant and antipsychotic drugs, predominantly serotonin and/or norepinephrine reuptake inhibitors and dopamine D2-antagonizing antipsychotic compounds, have several limitations. In addition, the exact pathophysiological mechanism leading to serotonergic, noradrenergic and dopaminergic dysfunction in psychotic disorders remains unclear. It has been postulated that an inflammatory mechanism may be involved in the pathogenesis of both depression and psychotic disorders. Furthermore, the differential activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and of the tryptophan/kynurenine metabolic pathway, resulting in the increased production of kynurenic acid in schizophrenia, and a possible increase in quinolinic acid in depression, also may play a key role in these diseases. Such differences are associated with an imbalance in glutamatergic neurotransmission that may contribute to increased levels of NMDA agonism in depression and NMDA antagonism in schizophrenia. In addition, immunological imbalance results in the increased production of PGE2 in schizophrenia and depression, as well as increased COX-2 expression in schizophrenia. Although there is evidence supporting the hypothesis that interactions between immune system components, IDO, the serotonergic system and glutamatergic neurotransmission play a key role in schizophrenia and depression, several gaps in knowledge remain, such as regarding the role of genetics, disease course, gender and different psychopathological states. There is evidence indicating that anti-inflammatory therapy may have beneficial effects in schizophrenia and major depression (MD). COX-2 inhibitors have been tested in animal models and in preliminary clinical trials, demonstrating favorable activity compared with placebo, both in schizophrenia and MD. However, the effects of COX-2 inhibition in the CNS, as well as toward different components of the inflammatory system, kynurenine metabolism and glutamatergic neurotransmission, require further evaluation, which should include clinical trials with larger numbers of patients. The potential inflammatory mechanism in schizophrenia and MD, and the possible therapeutic advantages of targeting this mechanism in the treatment of these disorders is discussed in this review.

 

 

More info:

http://www.ncbi.nlm....pubmed/20047157

http://www.medscape....warticle/760260

https://the-hive.arc...=&Number=518244

http://www.denvernat...news/cox-2.html

http://www.ncbi.nlm....pubmed/23305763

[PalmAnita]

Really interesting topic that I believe has much to promise! 

 

Curious is that both NMDA antagonism (e.g. ketamine) as well as -mild- NMDA agonism (e.g. sarcosine) seem to exhibit similar mood-lifting, antidepressant effects. Thinking about the possibly excitotoxic activity of excess glutamate / NMDA signalling, I am a bit wary about agonising NMDA receptors but while I'm trying to understand all the matter and have been studying it for quite a while, have to admit that I'm yet in the beginnings. 

 

I happen to react a bit different than one would expect to these things, with the right, low dosage of NMDA antagonists being truly and deeply relieving and nootropic in the sense of cognitive enhancement to me. There is some impact on memory most pronounced initially, but this goes away eventually and it's somewhat therapeutic in that it gives me distance to all the negative things, fears, depressive thoughts and such. Indeed I found 'dissociatives' aka NMDA antagonists to be very creative when used responsively and in sub-impacting dosages. They help me much with studying and understanding complex matter as well as foreign languages - in my 'sober' state of mind, I get distracted by thinking much too much in words, ending up with literal translations and such what makes it difficult to dive deeply into another language for example ... this fades away when the glutamate system is adjusted. It's hard to put this in words, but a truly estimable thing. Somehow I associate this state of mind with how children think - with most of the memories and maturity remaining. 

 

Unfortunately the only prescription NMDA antagonist memantine doesn't share these properties, while I find some use in it particularly as an anxiolytic and anti-obsessive / impulse-controlling agent (I'm overly sensitive and diagnosed with borderline personality, don't know what to think about) it seems not to have the pharmacology I desire.

 

I'm currently researching about the possible neurotoxic effects of prolonged NMDA antagonism that leads to some changes / damage in chronic heavy ketamine users visible on MRI imaging for example. Seems to be caused by NADPH oxidase, superoxides and oxidative stress and could be prevented by inhibiting the NAPDH oxidase partially - interesting fact that dextromethorphan is a NADPH oxidase inhibitor! - and/or by supplementing with N-acetylcysteine.

 

Certainly holds great promise for some currently treatment-resistant depressed people etc. (like me).

[sativa]

Indeed I found 'dissociatives' aka NMDA antagonists to be very creative when used responsively and in sub-impacting dosages. They help me much with studying and understanding complex matter as well as foreign languages - in my 'sober' state of mind, I get distracted by thinking much too much in words, ending up with literal translations and such what makes it difficult to dive deeply into another language for example ... this fades away when the glutamate system is adjusted. It's hard to put this in words, but a truly estimable thing. Somehow I associate this state of mind with how children think - with most of the memories and maturity remaining.

I totally agree with you here.

For example, in the past i would inhale small quantities of laughing gas (nitrous oxide) and enjoy the vastly expanded mind state it would bring about. Note nitrous oxide is an NMDA antagonist as well as mu opioid agonist.

Re child like state of being: NMDA antagonsism also features in Tryptamines (mushrooms etc) as of course ketamine. Both of these bring about this child like state of wonder and connection to the internal/external world. Also, dopamine 2 receptor plays a crucial role in this child like state, I believe there is an association between NMDA antagonsism and D2 receptor.

Of course, prolactin (which has an inverse relationship with dopamine) will also impact the ability to possess this child like state (the D2 aspect of it anyway).

Have you tried other NMDA antagonists like Theanine, agmatine?

[PalmAnita]

Yeah, things in the brain are all interconnected in a very complicated way - DA, 5-HT, NE, ACh, glutamate, endorphins ... think one can not look just at one isolated transmitter and try to understand the whole picture, this was required to start with but it led to some not-so-nice things like neuroleptics too. I used to associate energy, drive and motivation with dopamine, especially D2, but things seem to be a bit more difficult as the selective dopamine things like psychostimulants are qualitatively different and much more mechanic, rigid and hyper-focused than the creative, easy flowing energy I get from glutamate adjustments. 

 

Theanine doesn't do anything really noticeable for me unfortunately, but I've been quite curious about agmatine seeing that it's one of our endogen NMDA antagonists.. albeit a dirty one as it seems, it also negatively modulates AMPA receptors and might interfere with NADPH oxidase in a not exactly promising way if I'm right, but this is all just speculative for now. 

 

I know that many say the tryptamine / 5-HT2a agonists are capable of doing much the same as the dissociatives but in a somewhat oppositing way - might well be true, but I don't like the psychedelics. Might be due to genetics, no clue really, they tend do be much more chaotic, cold, confusing / psychotic and anxiogenic to me while the dissociatives are overall anxiolytic and induce positive feelings and thoughts. This is different for everybody, some get depressed from NMDA antagonists - I speculate it's partly because the experience is just 'alien' at first to many and the initial memory impairment together with all this speculation about Olney's lesions etc. leads to people fearing about brain damage that isn't really there at first hand.

 

NMDA antagonist neurotoxicity seems to be a real concern, but I'm not yet sure about it. Could be that it affects different individuals differently. That the depressed ones are less at risk when using responsible dosages because it just normalises brain activity - all the damage that has been studied was in people using more than 0.5 or even 1g of ketamine per day and over prolonged time. Not yet confirmed whether it's irreversible afaik.

 

But it's real, and possibly - this is where I'd really appreciate to read thoughts of more educated people about - avoidable thinking of the suggested mechanisms behind, oxidative stress originating from the NADPH oxidase etc.

 

Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase

Interleukin-6 Mediates the Increase in NADPH-Oxidase in the Ketamine Model of Schizophrenia

The NADPH Oxidase NOX2 Controls Glutamate Release: A Novel Mechanism Involved in Psychosis-Like Ketamine Responses

 

And the full text of an interesting paper linked on page 1: The kynurenine pathway and neurodegenerative disease 

Edited by dopamimetiq, 21 November 2015 - 11:17 AM.

[sativa]

Thanks, looks like I'm delving into NADPH this evening

[PalmAnita]

Also very remarkable is the recent research about N-acetylcysteine, it's role as an antioxidant that could well help protecting against these NADPH oxidase-originating issues. Showed interesting results in mental disorders like schizophrenia, bipolar depression etc.

 

So it could be a good thing to supplement NAC when using NMDA antagonists (?)

Facilitates vesicular dopamine release too!

 

N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action

Edited by dopamimetiq, 22 November 2015 - 08:46 AM.

[sativa]

Also very remarkable is the recent research about N-acetylcysteine, it's role as an antioxidant that could well help protecting against these NADPH oxidase-originating issues.
...
So it could be a good thing to supplement NAC when using NMDA antagonists (?)
Facilitates vesicular dopamine release too!

Oh good find!

Yes, NAC is great re dopamine.

It's funny, I acquired some DXM hBr recently!

Some NMDA antagonists:
*Zinc
*Garlic (S-Allyl Cysteine, a major component of garlic [a sulfur containing amino acid], Dimethyl Sulfoxide)
*PEA
*Parsley (Apigenin)

Iboga is another NMDA antagonist I occasionally use for neuronal maintenance.

Excitotoxic insult due to ibogaine leads to delayed induction of neuronal NOS in Purkinje cells.

Ibogaine causes degeneration of Purkinje cells (PKCs), presumably via activation of neurons in the inferior olive leading to release of glutamate at climbing fiber terminals. Following ibogaine administration, some Purkinje cells express NADPH-diaphorase and neuronal NOS (nNOS), neither of which is present normally in these cells. The induction of NOS is delayed in onset, dose-related, and detected in neurons adjacent to degenerated PKCs. The results demonstrate that nNOS induction can follow excitotoxic neuronal injury or perturbation. However, NO is unlikely to participate in the initial phase of PKC damage. Both the late induction of nNOS and the spatial relationship between damaged and nNOS-expressing PKCs are consistent with a role for NO in either neuronal recovery or delayed cell death following excitotoxic injury.

Also, an interesting phytochemical:

Kaempferol: This is a very potent CYP1A2 inhibitor. It’s also a potent MAO-A inhibitor. It also inhibits aldose reductase, xanthine oxidase, phenylalanine ammonia-lyase, tyrosinase, NADPH oxidase (NOX), Fatty Acid Synthase (FASN).

Kaempferol is a very potent superoxide scavenger, more potent than even quercetin.

Random info linking the sigma and NMDA systems: (DXM has activity at sigma 1 & 2)

Sigma1 receptors (and possibly sigma2) appear to be functionally coupled to some other receptors, notably nicotinic acetylcholine receptors (97,116) and NMDA receptors (106-109,275). They may actually be located on or near NMDA receptors (222).
...
The sigma2 receptor is less affected by DXM than the sigma1 receptor (58). Some of the sigma-induced potentiation of NMDA function may be due to sigma2 receptors (116). Ibogaine, currently being tested as a cure for heroin addiction, is a sigma2agonist (273,283). Other ligands for the sigma2receptor have been found (261,265,268).

[Mind_Paralysis]

 

Oh good find!


Some NMDA antagonists:
*Zinc
*Garlic (S-Allyl Cysteine, a major component of garlic [a sulfur containing amino acid], Dimethyl Sulfoxide)
*PEA
*Parsley (Apigenin)
 

Interesting. Is it by chance possible to put together an "NMDA-antagonist diet" with the help of information regarding these natural NMDA-antagonists and their availability in food-stuffs?

For instance, I imagine getting a decent NMDA-cocoa should be possible, since PEA is highly available in some strains of the cocoa-bean. (careful with some of that high-quality organic chocolate when on an MAOI! S'gonna' get you unexpectedly high as a 50-story building if you binge-eat it.)

 

 

Random info linking the sigma and NMDA systems: (DXM has activity at sigma 1 & 2)

 

You will find a lot more of these random info's - the NMDA-network is connected to nearly every neuronal system in the brain - it's involved in cognition on every level - hence why it pops up in studies of just about every brain-disorder there is.

IMHO nmda-mutations will be a big area of research in the future, with possible alternative indirect treatment-methods of many disorders.

[PalmAnita]

Iboga is another NMDA antagonist I occasionally use for neuronal maintenance.

 

 

 

Would you mind to share your experiences with ibogaine? I'm very curious about that molecule too, unfortunately it's being prohibited here where I live as another stupid blossom of our inglorious war on drugs, but I think the root bark is available nevertheless ... I'm somewhat wary of it because it seems to be a potent 5-HT2A agonist and they tend to be anxiogenic and chaotic for me, but as it's a NMDA antagonist it is promising for sure.

 

Yeah the sigma receptors are really obscure. Made me wonder about fluvoxamine, I don't like the SSRIs but as this one has the highest affinity for sigma-1, if it might have superior efficacy for some individuals? The antidepressant effects of DXM seem to be really linked to sigma, as co-administeration with a sigma antagonist abolished the AD-like effects at least in rodents.

[sativa]

Iboga is another NMDA antagonist I occasionally use for neuronal maintenance.

Would you mind to share your experiences with ibogaine?

Sure - well, I take it very sporadically, and the dosage is usually one or 2 drops. I have a full spectrum liquid (alcohol) extract.

As for what I feel...well its very subtle owing to the low dosage, but the following come to mind: internal calm, deep introspection, change of perspective.

I have used sub threshold doses of ketamine in the past to bring about a nice meditative state. Granted, ketamine is primarily NMDA antagonsism, D2 agonism and Mu opioid agonism (amongst other modes of action)

DXM hBr I have tried once also, and I intend to explore this molecule further. Here is a conglomerate of DXM's likely pharmacology. I don't have time to find and post links to research for this, but Google is available to all.

NMDA antagonist
D1, D2, D3, D5, dopamine reuptake
serotonin reuptake
norepinephrine reuptake
mu opioid agonist
sigma agonist (more so sigma 1; weak at sigma 2; unknown at sigma 3)
alpha-7 nicotinic acetylcholine antagonist
muscarinic antagonist

I have had incredible success with inhibiting KYNA metabolites using norharman derived from Syrian Rue seeds (Peganum Harmala)

What extraction did you use on the Syrian Rue seeds? Was it the acid/NaCl technique?

Saffron also is active at the sigma 1 site:

Planta Med. 2008 Jun;74(7):764-72. doi: 10.1055/s-2008-1074535. Epub 2008 May 21.

Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma (sigma-1) receptors.

...Saffron extracts and crocetin had a clear binding capacity at the PCP binding side of the NMDA receptor and at the sigma(1) receptor

Source: http://www.ncbi.nlm....pubmed/18496783

Edited by sativa, 17 January 2016 - 10:43 AM.

[YoungSchizo]

Does anyone have information on what Sarcosine might degrade into? I have some old Sarcosine from Smartpowders which was left unrefrigerated and possibly unsealed for a while. Could this be dangerous to take? Any help is appreciated.

Nothing to worry about, in the worst case you might die, that's all.

JK Imo it won't be life threatening or will make you sick, I think it just won't work. I'm not an expert though, If you don't trust it's safe to take simply toss it away. (I tried lots of supplements after their expiration, I'm talking years for some supps, even tried expired Sarcosine, never got sick though.)

[YoungSchizo]

Does anyone have information on what Sarcosine might degrade into? I have some old Sarcosine from Smartpowders which was left unrefrigerated and possibly unsealed for a while. Could this be dangerous to take? Any help is appreciated.

Nothing to worry about, in the worst case you might die, that's all.

JK Imo it won't be life threatening or will make you sick, I think it just won't work. I'm not an expert though, If you don't trust it's safe to take simply toss it away. (I tried lots of supplements after their expiration, I'm talking years for some supps, even tried expired Sarcosine, never got sick though.)

The reason I ask is because I've been feeling some mild irritability plus some mental fogginess from Sarcosine that I haven't experienced before. Sarcosine is a simple compound so I wouldn't think its degradation product could be that harmful.


At first, Sarcosine (with Glycine+NAC) seemed to act like the spark plug I was looking for. I could present my thoughts much more spontaneously and fluidly rather than forcing them. This effect has not gone away, even when I stopped Sarcosine for a week or two. But I struggle to find the dosing schedule for Sarcosine.


Now, my mind finds it difficult to stay focused on one point. Especially in class, too much stimuli can be overwhelming. I've been feeling irritable and restless as well. When I'm in a conversation, I'm not really listening to what the other person is saying but preformulating what I'm going to say next, so I end up interrupting them.

Maybe regular Sarcosine use pushes your NMDA receptors excessively and only needs to be taken every so often?

You might be on to something. Some of your symptoms like irritability, foginess and not being able to focus might as well be the result of taking too much Sarcosine than needed. Noticed it too when I was trying to find the right dosage for me, it disappeared when lowering plus I could keep taking it daily (used it for 4 years). Never experienced that stimuli was too overwhelming or that I had trouble with communication due to the use of Sarcosine. And yes, you can skip Sarcosine for days/weeks and it'll still keeps it effect.
I've quit Sarcosine completely, don't know if it is because of switching to another antipsychotic (Latuda) or that Sarcosine might have changed some things to my NMDA neurotransmitters but I don't need it anymore and when I take it, it causes sort of symptoms you describe or it does just nothing anymore. This is coming from someone in which Sarcosine changed his life/symptoms tremendously (I suffer from schizophrenia). On a side note, NAC exacerbate some of my symptoms badly, but many other schizo's benefit from it or the combo Sarcosine + NAC. My point with saying this is, adjust the use/dosage of Sarcosine and NAC and see if it makes any difference on your symptoms.

[YoungSchizo]

Forgot to mention, the symptoms that improved thanks to Sarcosine stayed like that. I've quit Sarcosine for over 6 months.

[sativa]

Regarding reduction of KYNA using Rosmarinic acid:

Inhibition of indoleamine-2,3-dioxygenase (IDO)

Rosmarinic acid also inhibits the expression of indoleamine-2,3-dioxygenase (IDO) via its cyclooxygenase inhibiting properties. Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway, thus causing depletion of tryptophan and serotonin production.

IDO is an immune checkpointmolecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophasgesand other immunoregulatory cells (also used as an immune subversion strategy by many tumors).

Inhibition of indoleamine 2,3-dioxygenase exerts neuroprotective properties by suppressing kyurenineneurotoxic metabolites such as quinolinic acid, 3-hydroxy-kynurenine and nitric oxide synthase.

Importantly, such inhibition may as well have notable affects on cognition, focus, mood, and related beneficial parameters, especially as it may be able to exert remediation of "brain fog" and related cognitive disturbances.

Edited by sativa, 19 February 2016 - 03:47 PM.

[sativa]

The human Pineal gland not only produces the remarkable neuro-hormone Melatonin, itself one of the body's most potent anti-oxidents, but the revolutionary Pinoline, which is the name for 6-methoxy-tetra-dydro-beta carboline, or 6-MeO-THBC for short.

Pegunam Harmala (aka Syrian Rue) also contains Pinolene.

Both Pinoline and Melatonin are instigators of mitosis; Pinoline is far superior to Melatonin in aiding DNA replication, and has potential to be involved in genetic programming and corrections of DNA damage.

PINOLINE AT SAME LEVEL AS MELATONIN IN THE EYE RETINA

The presence of two 5-methoxyindoles, 6-methoxy-1,2,3,4- tetrahydro-beta-carboline (6-MeO- THBC ) and melatonin was demonstrated in human retinae using a highly specific gas chromatographic mass spectrometric method from eyes affected with various ocular diseases. Both compounds were found to occur in similar quantities. 6-MeO- THBC is a newly- identified endogenously-occurring retinal compound possibly acting as a neuromodulator.

-Dr. M. Leino: 6-Methoxy-tetrahydro-beta-carboline and melatonin in the human retina.: Exp Eye Res: 38:3:325-30 (1984)


BETA CARBOLINES AS ANTI-OXIDENTS

A series of 1,2,3,4-tetrahydro-beta-carbolines has been synthesized and evaluated for cerebral protecting effects against lipid peroxidation and potassium cyanide intoxication in mice. Most of the compounds synthesized had potent effects against lipid peroxidation. Among them, 1- (3,5-dimethoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta- carboline (22) was found to have a combination of potent effects against both lipid peroxidation and potassium cyanide intoxication.

Kawashima Y; Horiguchi A; Taguchi M; Tuyuki Y; Karasawa Y; Araki H; Hatayama K: Synthesis and pharmacological evaluation of 1,2,3,4-tetrahydro-beta-carboline derivatives.: Chem Pharm Bull (Tokyo): 43:5:783-7 (1995)


PINOLINE ANTI-ADDICTIVE

Melatonin's active metabolite Pinoline is oneirogenic. Not only have such beta carbolines been shown to have, via the NMDA receptor, an anti-addictive effect against opiates and stimulants such as cocaine.

Additional REM in the morning for people who are REM-deprived may bring about a 25% rise in serotonin uptake.

-Dr. J. C. Callaway, Mechanism For Visions of Dream Sleep. Department of Pharmacology & Toxicology, University Of Koupio, Finland


PINOLINE FOR PARKINSONS + ALZHEIMERS DISEASE

The progression of several neurological diseases such as Alzheimer's disease and Parkinson's disease has recently been shown to involve free radical damage. It is therefore of great importance to find agents that will effectively protect brain tissue against oxidative damage. The purpose of this study was to evaluate the free radical scavenging properties of pinoline.

The results found in this study suggest that both melatonin and pinoline are valuable as potential free radical scavengers in brain tissue.

Both pinoline and melatonin were found to inhibit lipid peroxidation in a dose-dependent manner.

Frederiksen T; Pless G: Antioxidantive potential of melatonin and pinoline in lipid peroxidation of brain tissue: Master's thesis: 1-52, App. (1998)


PINOLINE CURES DERMATOSIS IS ANTI-FUNGAL & ANTI BACTERIAL

The extract of Peganum harmala (Rutaceae) was used topically to treat certain dermatoses of inflammatory nature. Results were encouraging and proved the antibacterial, antifungal, antipruritic and probably antiprotozoal effects of the extract.

-Peganum harmala: its use in certain dermatoses. El-Saad El-Rifaie M

Insight into melatonin, mitosis and sleep:

Now it is a well known fact in science that Melatonin induces metosis. Melatonin does this, by sending a small electrical signal up the double helix of the DNA, which instigates an 8 HZ proton signal that enables the hydrogen bonds to the stair steps, to zip open, and the DNA can replicate.

This is astonunding unto itself. Melatonin is exclussively made in the Pineal Galnd, comprised of the same Tryptophane base materials as Pinoline, in fact Pinoline is made in two steps from Melatonin, but the pineal gland uses another pathway to produce Pinoline as well, in about equal quantities to Melatonin. Since Melatonin we only produce in sufficient quantitites in darkness whilst we sleep, darkness is essential for our body to reproduce.

And rue also contains flavonoids:

FOUR FLAVONOID GLYCOSIDES FROM PEGANUM HARMALA

The aerial parts of Peganum harmala yielded four new flavonoids: acacetin 7-O-rhamnoside,7-O-[6"-O-glucosyl-2"-O-(3'''-acetylrhamnosyl)glucoside and 7-O-(2'''-O-rhamnosyl-2"-O-glucosylglucoside), and the glycoflavone 2'''-O-rhamnosyl-2"-O-glucosylcytisoside.

-Sharaf M, el-Ansari MA, Matlin SA, Saleh NA, National Research Centre, Cairo, Egypt. PMID: 9014375, UI: 97166655

Edited by sativa, 22 March 2016 - 08:01 PM.

[sativa]

http://www.ncbi.nlm....pubmed/23063682

Natural inhibitors of indoleamine 3,5-dioxygenase induced by interferon-gamma in human neural stem cells.

Indoleamine dioxygenase (IDO) is a heme-containing enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine, kynurenine and the downstream quinolinic acid. Though IDO is physiologically important in maintaining tissue integrity, aberrant IDO expression represses T cell function and promotes regulatory T cells (Treg) in cancer. It additionally exacerbates Alzheimer, depression, Huntington and Parkinson diseases via quinolinic acid.

Inhibition of IDO has thus been recently proposed as a strategy for treating cancer and neuronal disorders. In the present study, we have developed a cell-based assay to evaluate the suppressive effect of anti-inflammatory phytochemicals on the enzyme. When stimulated by INF-γ, profound high expressions of IDO-1 mRNA as well as the protein were detected in human neural stem cells (hNSC) and verified by real-time retro-transcribed PCR and western blot analysis, respectively. The protein activity was measured by kynurenine concentration and the assay was validated by dose-responsive inhibition of IDO-1 antagonists including 1-methyltryptaphan, indomethacin and acetylsalicylic acid.

Among the tested compounds, apigenin, baicalein, chrysin, and wogonin exhibit a potent repressive activity with IC(50s) comparable to that of indomethacin. The inhibition was further found to be independent of gene expression and protein translation because of the unaltered levels of mRNA and protein expression. Although curcumin displayed a potent inhibitory activity to the enzyme, it appeared to be cytotoxic to hNSCs. Morphological examination of hNSC revealed that baicalein and wogonin at the inhibitory concentrations induced neurite outgrowth.

In conclusion, our data shows that certain phytochemicals with 2-phenyl-1-benzopyran-4-one backbone (flavones) attenuate significantly the IDO-1 protein activity without harming hNSCs. The inhibitory activity might have partially contributed to the anti-cancer and neuro-protective property of the compounds.

[jack black]

Regarding reduction of KYNA using Rosmarinic acid:
 

Inhibition of indoleamine-2,3-dioxygenase (IDO)

Rosmarinic acid also inhibits the expression of indoleamine-2,3-dioxygenase (IDO) via its cyclooxygenase inhibiting properties. Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway, thus causing depletion of tryptophan and serotonin production.

IDO is an immune checkpointmolecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophasgesand other immunoregulatory cells (also used as an immune subversion strategy by many tumors).

Inhibition of indoleamine 2,3-dioxygenase exerts neuroprotective properties by suppressing kyurenineneurotoxic metabolites such as quinolinic acid, 3-hydroxy-kynurenine and nitric oxide synthase.

Importantly, such inhibition may as well have notable affects on cognition, focus, mood, and related beneficial parameters, especially as it may be able to exert remediation of "brain fog" and related cognitive disturbances.

 

 

Interesting info, but keep in mind that inhibiting IDO suppresses the neurotoxic quinolinic acid and  3-hydroxy-kynurenine but has no impact on KYNA itself (that is neuroprotective).

 

IMHO, the whole idea about supressing KYNA is misguided. if the premise of it was true, schizophrenics would have superpowers and we know they don't (or do they?).

 

http://www.ncbi.nlm....pubmed/23063682

Natural inhibitors of indoleamine 3,5-dioxygenase induced by interferon-gamma in human neural stem cells.

Indoleamine dioxygenase (IDO) is a heme-containing enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine, kynurenine and the downstream quinolinic acid. Though IDO is physiologically important in maintaining tissue integrity, aberrant IDO expression represses T cell function and promotes regulatory T cells (Treg) in cancer. It additionally exacerbates Alzheimer, depression, Huntington and Parkinson diseases via quinolinic acid.

Inhibition of IDO has thus been recently proposed as a strategy for treating cancer and neuronal disorders. In the present study, we have developed a cell-based assay to evaluate the suppressive effect of anti-inflammatory phytochemicals on the enzyme. When stimulated by INF-γ, profound high expressions of IDO-1 mRNA as well as the protein were detected in human neural stem cells (hNSC) and verified by real-time retro-transcribed PCR and western blot analysis, respectively. The protein activity was measured by kynurenine concentration and the assay was validated by dose-responsive inhibition of IDO-1 antagonists including 1-methyltryptaphan, indomethacin and acetylsalicylic acid.

Among the tested compounds, apigenin, baicalein, chrysin, and wogonin exhibit a potent repressive activity with IC(50s) comparable to that of indomethacin. The inhibition was further found to be independent of gene expression and protein translation because of the unaltered levels of mRNA and protein expression. Although curcumin displayed a potent inhibitory activity to the enzyme, it appeared to be cytotoxic to hNSCs. Morphological examination of hNSC revealed that baicalein and wogonin at the inhibitory concentrations induced neurite outgrowth.

In conclusion, our data shows that certain phytochemicals with 2-phenyl-1-benzopyran-4-one backbone (flavones) attenuate significantly the IDO-1 protein activity without harming hNSCs. The inhibitory activity might have partially contributed to the anti-cancer and neuro-protective property of the compounds.

 

 

This is so very cool. Thanks for posting. Now I understand why anti-inflammatory drugs are neuroprotective.

[jack black]

 

IMHO, the whole idea about supressing KYNA is misguided. if the premise of it was true, schizophrenics would have superpowers and we know they don't (or do they?).

 

 

 

 

LOL, stupid mistake. Schizo=high KYNA, ADHD=low KYNA. So, i really meant ADHD having superpowers. But actually they do. There is this paradoxal hyperattention phenomenon in ADHD. Maybe this is what the OP is after?