Newly identified pathway provides insight into long COVID brain fog

[Wishful]

https://newatlas.com/medical/newly-identified-pathway-provides-insight-into-long-covid-brain-fog/

The study points to the kynurenine pathway as being involved in brainfog. I haven't read the actual study, but I see this as something that should prompt further studies. Of course, researchers seem to dislike doing follow-up studies, so is this sort of discovery actually a bad thing?

My personal observations of my ME have long pointed to involvement of the kynurenine pathway, so of course I'm willing to accept the findings of this study.

 

[hapl808]

The study is beyond me to read at the moment, but here's a ChatGPT breakdown of how it would be relevant for treatment as opposed to biomarker identification. (Obviously like all LLM, take with a grain of salt.)

The study suggests that there is a significant prevalence of cognitive impairment following acute COVID-19 infection, persisting up to 12 months post-infection. This cognitive impairment is correlated with markers in the kynurenine pathway (KP), particularly elevated levels of quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, and the kynurenine/tryptophan ratio. These KP metabolites are also linked to post-acute sequelae of COVID-19 (PASC). This opens up possibilities for both biomarkers to assess long-term cognitive effects and therapeutic interventions targeting the kynurenine pathway.

Therapeutic Targets:​

1. Inhibition of KP Enzymes: Compounds like 1-methyltryptophan can inhibit indoleamine 2,3-dioxygenase (IDO), an enzyme involved in KP.
   • Pros: May reduce KP activation.
   • Cons: Not yet validated for this specific application.
2. Kynurenine 3-Monooxygenase (KMO) Inhibitors: These could prevent the conversion of kynurenine to 3-hydroxykynurenine.
   • Pros: Targeted effect.
   • Cons: Limited clinical data.
3. Antagonists to NMDA Receptor: Since quinolinic acid is an NMDA receptor agonist, blocking this receptor might help.
   • Pros: Well-understood class of drugs like memantine.
   • Cons: Broad effects on the CNS.
4. AhR Inhibitors: Compounds like CH-223191 can inhibit Aryl Hydrocarbon Receptor, which is activated by some KP metabolites.
   • Pros: Could target KP at another level.
   • Cons: May have off-target effects.
5. IFN-beta Inhibitors: Given that IFN-beta was linked to prolonged KP activation, it might be a therapeutic target.
   • Pros: Could offer upstream inhibition.
   • Cons: May affect immune response adversely.

Potential Oral or Nasal Medications or Supplements:​

1. 1-Methyltryptophan: Oral, to inhibit IDO.
2. Memantine: Oral, NMDA receptor antagonist.
3. CH-223191: Likely oral, to inhibit AhR.
4. Steroids: Oral/Intranasal, as broad immunosuppressants might downregulate IFN-beta.
5. Tryptophan Supplements: To balance the kynurenine/tryptophan ratio, although this is highly speculative.

Always consult healthcare providers for personalized medical advice and treatment.

 

[datadragon]

This cognitive impairment is correlated with markers in the kynurenine pathway (KP), particularly elevated levels of quinolinic acid, 3-hydroxyanthranilic acid, kynurenine,

It was recently found that Butyrate ameliorates quinolinic acid-induced cognitive decline in inflammatory obesity models https://pubmed.ncbi.nlm.nih.gov/36787221/ and previously, it was reported that butyrate improved memory in Alzheimer's Disease mouse models https://pubmed.ncbi.nlm.nih.gov/21593570

Butyrate also represses IDO-1 expression by two distinct mechanisms. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297836/ Butyrate is one of the short-chain fatty acids (SCFAs), metabolites found low in ME/CFS. Quinolinic acid is associated with cognitive deficits in schizophrenia and other inflammatory conditions (not just ME/CFS) https://www.nature.com/articles/s41598-021-89335-9 as well as brain fog https://www.treatlyme.net/guide/brain-fog-lyme-disease

The active form of Vitamin B6 (PLP) is an essential cofactor in the kynurenine pathway (along with B2 Riboflavin). https://www.researchgate.net/figure...nurenine-pathway-73-Kynurenine_fig2_318623658 Adequate intake of these vitamins has been associated with production of kynurenic acid which inhibits NLRP3 activation https://pubmed.ncbi.nlm.nih.gov/36311752/ rather than quinolinic acid, which acts as an agonist to the Glutamate NMDA receptor, Zinc is involved with active B6 and getting active B6 into the cell and Zinc uptake is also lowered and less available to utilize during inflammation.

Quinolinic acid (QUIN) and kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the excitatory amino acid N-methyl-D-aspartate (NMDA) receptor. Quinolinic acid (quinolinate) – endogenous glutamate site NMDA agonist. Kynurenic acid – endogenous glycine site NMDA antagonist. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function via an allosteric glycine site. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr https://www.ncbi.nlm.nih.gov/pubmed/16787837/ Understanding the mechanisms will help to develop or point to drugs or target supplements to try better.

 

[Rufous McKinney]

Of course, researchers seem to dislike doing follow-up studies, so is this sort of discovery actually a bad thing?

yes, that.

We've been told that nobody will want to publish THAT, if the result are ever mentioned in passing.

And nobody ever funds the LARGER SCALE study required to go to any NEXT step.

Why follow up? No glory in that.

And what is a diagnostic test? Anybody ever try to establish any of those?

 

[Rufous McKinney]

Understanding the mechanisms will help to develop or point to drugs or target supplements to try better.

This seems like really important "findings"...

I hope to read thru it, once I find a way out of the brain fog I'm wandering in, these days.

I need somebody with a functional Brain to work this up into an RX for how do we simply attempt to address this.

For instance, since I"m mentally impaired today, but might be more functional once I"m not crashed....

Is this saying we want less tryptophan in our brains or more?

"Potential Oral or Nasal Medications or Supplements:​

1. 1-Methyltryptophan: Oral, to inhibit IDO.
2. Memantine: Oral, NMDA receptor antagonist.
3. CH-223191: Likely oral, to inhibit AhR.
4. Steroids: Oral/Intranasal, as broad immunosuppressants might downregulate IFN-beta.
5. Tryptophan Supplements: To balance the kynurenine/tryptophan ratio, although this is highly speculative.

Always consult healthcare providers for personalized medical advice and treatment."

some of us were reducing the tryptophan with BCAAs. Is this saying take more Tryptophan?

 

[Wishful]

BCAAs only reduce transport of TRP across the BBB temporarily, so it's not really a treatment for reducing TRP. It blocked the abrupt increase in symptoms I had gotten 20 minutes after eating carbs, but it was probably just spreading the increase out over time.

I wanted to try 1methyltryptophan, just to see what effect it had, but it wasn't easy to get. There was another pro-drug under development that also inhibited KYN production via IDO; I think it was 4 or 7-formylkunurenine, but that too wasn't available for experimenting with.

I don't think TRP supplements will change the KYN/TRP ratio, or at least not for long, since more TRP will mean more KYN, and the ratio depends on the mechanisms doing the conversion.

For anyone thinking of trying a reduced-TRP diet, I tried a near-zero TRP diet for a year or so, with no noticeable benefits. I think our bodies have too big reserve capacity and too efficient scavenging of TRP to affect KYN levels that way.

 

[Rufous McKinney]

BCAAs only reduce transport of TRP across the BBB temporarily,

thanks for helping clarify that....

I want to try the BCAA's again, because it seemed like they were sort of helping me back in 2019.....

 

[datadragon]

Age-related decreases in the GLUTAMATE NMDA NR2B subunit correlate with memory deficits. Both mice and rats that were engineered to over-express GRIN2B in their brains have increased mental ability, learning faster and remembering better. The "Doogie" mouse had double the learning ability. Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the GRIN2B gene. NR2B interestingly is also linked to depression and neuropathic pain when high.

Sodium Butyrate inhibits IDO1 and here increased NR2B and lowered pro inflammatory cytokines and therefore might be one to consider for some https://www.sciencedirect.com/science/article/abs/pii/S0009279721000880 and improved memory in Alzheimer's Disease mouse models in later stages (mentioned earlier)

Active B6 appears to as well
https://pubmed.ncbi.nlm.nih.gov/28872356/ The active form of Vitamin B6 (P5P) (but not pyridoxine) prevents IL-1β production by inhibiting NLRP3 inflammasome activation and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome https://pubmed.ncbi.nlm.nih.gov/27733681/ (but not pyridoxine form which competitively inhibits the active form. https://www.sciencedirect.com/science/article/abs/pii/S0887233317301959?via=ihub

It also appears to require balance. Both insufficient and excessive levels of IL-1β (which is increased after NLRP3 activation) impair the formation of memory indicating that IL-1β is important for normal learning and memory formation and would explain all the mixed results. The involvement of IL-1 in hippocampal-dependent memory follows an inverted U-shaped pattern, i.e., a slight increase in brain IL-1 levels can improve memory, whereas any deviation from the physiological range, either by excess elevation in IL-1 levels or by blockade of IL-1 signaling, results in impaired memory. https://www.ncbi.nlm.nih.gov/pubmed/17976923/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560336/pdf/12264_2010_Article_6023.pdf

Quinolinic acid (quinolinate) – endogenous glutamate site NMDA agonist (increase). Kynurenic acid – endogenous glycine site NMDA antagonist (decrease). Going in the other direction, Serotonin, by activating 5-HT(1A) 5-hydroxytryptamine receptor 1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT(1A) receptors https://pubmed.ncbi.nlm.nih.gov/15944377/ Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex https://pubmed.ncbi.nlm.nih.gov/18442977/ Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594018/ So it appears that this pathway is very involved in the regulation of NMDA NR2B. https://forums.phoenixrising.me/thr...nfa-itaconate-shunt-part-2.89388/post-2438998

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit Again points to balance as too much Kynurenic acid which lowers or too much Quinolinic acid which raises are both problematic. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325545/

It also appears that the loss of Shank3 via zinc deficiency that is required for its function or lowered from NLRP3 over activation interacts with NMDA receptors. This can also have a downstream effect on Vitamin B6. Since SHANK3 is concentrated in glutamatergic synapses, it interacts with all prominent glutamate receptors, such as NMDA, AMPA, and mGlu receptors. SHANK3 also indirectly interacts with Neuroligins (NLGN), a family of post-synaptic adhesion molecules. Most of these interactions are indirect and mediated by post-synaptic proteins such as GKAP, Homer PSD95 etc. InsG3680 Shank3 mutant mice show disruptions of glutamatergic signaling as compared to WT controls. https://www.nature.com/articles/s41398-021-01612-3

 

[Wishful]

It also appears to require balance.

Yes, we have so many biological mechanisms depending on having just the right balance of factors. These involve feedback loops to maintain homeostasis. ME seems to be trying to maintain the abnormal state: treatments work for a short time before the body adapts and reasserts the abnormal state. That's why I believe that ME is one of these feedback mechanisms malfunctioning. I'm familiar with electronic feedback circuits, and if I imagine the body as millions of op-amp circuits linked together, it's easy to imagine just one component shifting value a bit causing the whole system to lock into a different state.

but not pyridoxine form which competitively inhibits the active form.

That still allows pyroxidine to be a useful experiment: if taking it doesn't make a difference in symptoms, then the active form, being inhibited, isn't a significant factor in ME. Pyroxidine doesn't do anything for my ME symptoms.

 

[datadragon]

ME seems to be trying to maintain the abnormal state: treatments work for a short time before the body adapts and reasserts the abnormal state.

Hi Wishful, One example to understand that better was both vancomycin and amoxicillin (not others) showed improvement with Autism back when it was far less understood. https://pubmed.ncbi.nlm.nih.gov/10921511/ But then unfortunately the improvements were temporary and waned on later follow up after it was stopped. It turns out the temporary reduction in propionic acid gave relief from those specific antibiotics which was leading to the symptoms, but did not 'fix' the actual cause of the ongoing imbalances that caused the ongoing high propionic acid and low butyrate as a downstream effect in the first place, so it returned upon the antibiotic stoppage. That is why you may get results sometimes targeting a downstream pathway that is dysregulated. This just means that we sometimes are only working on one specific downstream area/pathway which may help certainly if that pathway activation or inhibition is helpful, but not necessarily fix all the other areas that are not working properly that are also dysregulated such as al the other different functions of a missing nutrient like zinc or SCFA like butyrate or reducing the inflammation leading to those issues in the first place.

Briefly, there is a gut dysbiosis with higher levels of propionate and lower butyrate in those with autism and I learned much later that vancomycin eradicated the propionic acid producing bacteria and reduced the propionate level in fecal samples from a child with propionic acidemia. ASD features and ASD have been reported also in patients with propionic acidemia caused by propionic acid (PPA) accumulation due to propionyl-CoA carboxylase enzyme deficiency https://adc.bmj.com/content/archdischild/82/2/169.full.pdf

That still allows pyroxidine to be a useful experiment: if taking it doesn't make a difference in symptoms, then the active form, being inhibited, isn't a significant factor in ME. Pyroxidine doesn't do anything for my ME symptoms.

Active B6 involves zinc and therefore can be yet another downstream effect of the zinc being lowered. Lets say you could take active B6 in a supplement, it may still not get into the cell apparently due to a low zinc and just build up levels, and this doesnt fix the low Vitamin A -> copper -> iron, loss of glutathione or increase in propionic acid and low butyrate since your taking B6 but not fix the cause of the low B6 leading to all those issues. The point is trying to explain that multiple things can become dysregulated as downstream effects and as above, targeting only one piece cant fix all of them. In autism taking butyrate or drug HDAC inhibitors do help so its possible that in some cases, targeting only one area will work fine and therefore drugs or supplements will help, but otherwise in some conditions it may require knowing more about the entire process to target it at the earliest points possible to prevent all the subsequent downstream effects.

PS - I think they are saying pyridoxine form is also toxic, so it seems best to avoid in larger than RDA doses like through supplements. Normally in small amounts it would be converted, but this may not be happening under chronic inflammation or infection.

 

[Alvin2]

Memantine: Oral, NMDA receptor antagonist.

I have a bottle of this floating around, long story.
I don't have the courage to try it for ME.

 

[Violeta]

Age-related decreases in the GLUTAMATE NMDA NR2B subunit correlate with memory deficits. Both mice and rats that were engineered to over-express GRIN2B in their brains have increased mental ability, learning faster and remembering better. The "Doogie" mouse had double the learning ability. Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the GRIN2B gene. NR2B interestingly is also linked to depression and neuropathic pain when high.

Sodium Butyrate inhibits IDO1 and here increased NR2B and lowered pro inflammatory cytokines and therefore might be one to consider for some https://www.sciencedirect.com/science/article/abs/pii/S0009279721000880 and improved memory in Alzheimer's Disease mouse models in later stages (mentioned earlier)

Active B6 appears to as well
https://pubmed.ncbi.nlm.nih.gov/28872356/ The active form of Vitamin B6 (P5P) (but not pyridoxine) prevents IL-1β production by inhibiting NLRP3 inflammasome activation and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome https://pubmed.ncbi.nlm.nih.gov/27733681/ (but not pyridoxine form which competitively inhibits the active form. https://www.sciencedirect.com/science/article/abs/pii/S0887233317301959?via=ihub

It also appears to require balance. Both insufficient and excessive levels of IL-1β (which is increased after NLRP3 activation) impair the formation of memory indicating that IL-1β is important for normal learning and memory formation and would explain all the mixed results. The involvement of IL-1 in hippocampal-dependent memory follows an inverted U-shaped pattern, i.e., a slight increase in brain IL-1 levels can improve memory, whereas any deviation from the physiological range, either by excess elevation in IL-1 levels or by blockade of IL-1 signaling, results in impaired memory. https://www.ncbi.nlm.nih.gov/pubmed/17976923/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560336/pdf/12264_2010_Article_6023.pdf

Quinolinic acid (quinolinate) – endogenous glutamate site NMDA agonist (increase). Kynurenic acid – endogenous glycine site NMDA antagonist (decrease). Going in the other direction, Serotonin, by activating 5-HT(1A) 5-hydroxytryptamine receptor 1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT(1A) receptors https://pubmed.ncbi.nlm.nih.gov/15944377/ Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex https://pubmed.ncbi.nlm.nih.gov/18442977/ Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594018/ So it appears that this pathway is very involved in the regulation of NMDA NR2B. https://forums.phoenixrising.me/thr...nfa-itaconate-shunt-part-2.89388/post-2438998

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit Again points to balance as too much Kynurenic acid which lowers or too much Quinolinic acid which raises are both problematic. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325545/

It also appears that the loss of Shank3 via zinc deficiency that is required for its function or lowered from NLRP3 over activation interacts with NMDA receptors. This can also have a downstream effect on Vitamin B6. Since SHANK3 is concentrated in glutamatergic synapses, it interacts with all prominent glutamate receptors, such as NMDA, AMPA, and mGlu receptors. SHANK3 also indirectly interacts with Neuroligins (NLGN), a family of post-synaptic adhesion molecules. Most of these interactions are indirect and mediated by post-synaptic proteins such as GKAP, Homer PSD95 etc. InsG3680 Shank3 mutant mice show disruptions of glutamatergic signaling as compared to WT controls. https://www.nature.com/articles/s41398-021-01612-3

This is what I am trying to understand now, quinolinic acid, etc., and so interesting that zinc (and B6) are involved.

 

[datadragon]

This is what I am trying to understand now, quinolinic acid, etc., and so interesting that zinc (and B6) are involved.

Yes, the info is a bit higher up https://forums.phoenixrising.me/thr...-into-long-covid-brain-fog.90640/post-2441810 Its starting to make more sense when I was looking at it more as the body is shifting to an inflammatory state like a see saw, all these different areas we are looking at are linked as part of that. For example zinc is involved with b6 which would otherwise lower nlrp3 inflammasome (inflammation) also, involved with Vitamin A metabolism which normally would be involved with ceruloplasmin production to make our copper and iron usable, High homocysteine induces endoplasmic reticulum (ER) stress https://pubmed.ncbi.nlm.nih.gov/15243582/ (which increases WASF3 levels that induce exercise intolerance), but it also increases NLRP3 inflammasome and downregulates peroxisome proliferator-activated receptor (PPAR) expression (PPAR-a and PPAR-y) https://pubmed.ncbi.nlm.nih.gov/28394319/ https://link.springer.com/article/10.1186/1475-2891-3-4 . zinc is needed for ppars, zinc deficiency Im finding is capable of inducing the itaconate shunt that Dr Phair was working on, which inhibits B12 and therefore blocking methylation pathways subsequently increasing homocysteine so it all again is a shift to an inflammatory state. zinc was a cofactor for glutathione, but with that down b12 also would take the hit as a substitute reducing levels further increasing homocysteine. B6 can further lower homocysteine etc. https://forums.phoenixrising.me/threads/staggering-incompetence.90602/post-2444374

 

[Violeta]

Yes, the info is a bit higher up https://forums.phoenixrising.me/thr...-into-long-covid-brain-fog.90640/post-2441810 Its starting to make more sense when I was looking at it more as the body is shifting to an inflammatory state like a see saw, all these different areas we are looking at are linked as part of that. For example zinc is involved with b6 which would otherwise lower nlrp3 inflammasome (inflammation) also, involved with Vitamin A metabolism which normally would be involved with ceruloplasmin production to make our copper and iron usable, High homocysteine induces endoplasmic reticulum (ER) stress https://pubmed.ncbi.nlm.nih.gov/15243582/ (which increases WASF3 levels that induce exercise intolerance), but it also increases NLRP3 inflammasome and downregulates peroxisome proliferator-activated receptor (PPAR) expression (PPAR-a and PPAR-y) https://pubmed.ncbi.nlm.nih.gov/28394319/ https://link.springer.com/article/10.1186/1475-2891-3-4 . zinc is needed for ppars, zinc deficiency Im finding is capable of inducing the itaconate shunt that Dr Phair was working on, which inhibits B12 and therefore blocking methylation pathways subsequently increasing homocysteine so it all again is a shift to an inflammatory state. zinc was a cofactor for glutathione, but with that down b12 also would take the hit as a substitute reducing levels further increasing homocysteine. B6 can further lower homocysteine etc. https://forums.phoenixrising.me/threads/staggering-incompetence.90602/post-2444374

All I can say is WOW.

 

[Violeta]

All I can say is WOW.

Are you on Twitter (X)? @Manuel has very good information.

https://x.com/manruipa/status/1703705925922472145?s=20

 

[Violeta]

I have fairly recently started to have more cavities, and just noticed that gum recession is excellerating.

I saw some info about zinc (and C) being essential for gum and dental health, and will definitely pay more attention to getting adequate amounts of both on a daily basis.

I also am wondering if having had COVID is affecting my zinc levels, making it more difficult to maintain adequate supply, and am wondering if besides taking adequate B6, which is in my B Complex and several times a week taking a little extra, if there is anything else that should be added to the mix.

I don't know what specifically about COVID messes up zinc levels so badly, but I'll keep looking.

 

[Gondwanaland]

I have fairly recently started to have more cavities, and just noticed that gum recession is excellerating.

I saw some info about zinc (and C) being essential for gum and dental health, and will definitely pay more attention to getting adequate amounts of both on a daily basis.

I also am wondering if having had COVID is affecting my zinc levels, making it more difficult to maintain adequate supply, and am wondering if besides taking adequate B6, which is in my B Complex and several times a week taking a little extra, if there is anything else that should be added to the mix.

I don't know what specifically about COVID messes up zinc levels so badly, but I'll keep looking.

Zinc is frequently understimated. I reacted badly to it many times in the past - picolinate was just awful, glycinate made me sleepy when taken in the morning and wide awake when taken at dinner, finally I settled with citrate after horrible insomnia and starting over at 1 mg and titrating it up to 10 - 15 mg daily in the morning.

Right now I take Zn gluconate. What really helped me was this:

-I bought liquid zinc gluconate (drops for kids 2 mg/drop)

-I started with 1 drop for a couple of days and slowly increased to 5 drops.

Nowadays I take 3 - 4 drops daily, on and off.

This form of zinc smells like stinky feet, and it oddly caused me a probable viral outbreak on my lower lip when I started taking it, which I promptly resolved with a lysine solution (I diluted lysine powder in a little bit of water and dabbed on my lip). It didn't look like the regular blistering herpes though, anyway...

So all this long story was to say that taking zinc helped me to better absorb B6. Improving B6 metabolism also improves magnesium absorption and utilization.

When I first tried P5P it felt like a cure-all, but it only lasted 2 weeks and I crashed. It seems to me that P5P works like a corticoid drug suppressing adrenals.

I believe all these pathways are blocked for some reason, and to me it seems that zinc might be the key to open them up.

Additionally, I never tolerated Taurine either (same as Zn glycinate), but recently I found out that magnesium taurate is very good for sleep.

Long ago I had a very positive experience with magnesium oxide - well documented here in this forum - followed by long years of intoleration to Mg supplements.

After I caught covid for the 2nd time my body started begging for magnesium and now I am able to take it again in small doses (30 - 50 mg) as long as it is bound to Taurine, which is GABAergic - and perhaps also helps with protein misfolding? Sometimes for better sleep I also add some Mg glycinate to it, but it must be in a much smaller amount than the Mg taurate.

 

[Violeta]

Zinc is frequently understimated. I reacted badly to it many times in the past - picolinate was just awful, glycinate made me sleepy when taken in the morning and wide awake when taken at dinner, finally I settled with citrate after horrible insomnia and starting over at 1 mg and titrating it up to 10 - 15 mg daily in the morning.

Right now I take Zn gluconate. What really helped me was this:

-I bought liquid zinc gluconate (drops for kids 2 mg/drop)

-I started with 1 drop for a couple of days and slowly increased to 5 drops.

Nowadays I take 3 - 4 drops daily, on and off.

This form of zinc smells like stinky feet, and it oddly caused me a probable viral outbreak on my lower lip when I started taking it, which I promptly resolved with a lysine solution (I diluted lysine powder in a little bit of water and dabbed on my lip). It didn't look like the regular blistering herpes though, anyway...

So all this long story was to say that taking zinc helped me to better absorb B6. Improving B6 metabolism also improves magnesium absorption and utilization.

When I first tried P5P it felt like a cure-all, but it only lasted 2 weeks and I crashed. It seems to me that P5P works like a corticoid drug suppressing adrenals.

I believe all these pathways are blocked for some reason, and to me it seems that zinc might be the key to open them up.

Additionally, I never tolerated Taurine either (same as Zn glycinate), but recently I found out that magnesium taurate is very good for sleep.

Long ago I had a very positive experience with magnesium oxide - well documented here in this forum - followed by long years of intoleration to Mg supplements.

After I caught covid for the 2nd time my body started begging for magnesium and now I am able to take it again in small doses (30 - 50 mg) as long as it is bound to Taurine, which is GABAergic - and perhaps also helps with protein misfolding? Sometimes for better sleep I also add some Mg glycinate to it, but it must be in a much smaller amount than the Mg taurate.

Oh boy, very helpful. I have zinc carnosine, which I only took two times, with and without food, and both times it cause a bad reaction. I have zinc picolinate but haven't tried it yet, will be interesting to see how that goes.

Just found a bottle of magnesium taurate in my husband's stash, looking forward to see how I do with that!

If I can't get used to either of them, I will try a bottle of the zinc gluconate drops.

Thank you, @Gondwanaland, my brain feels fried today and I needed some help.

 

[Gondwanaland]

Oh boy, very helpful. I have zinc carnosine, which I only took two times, with and without food, and both times it cause a bad reaction. I have zinc picolinate but haven't tried it yet, will be interesting to see how that goes.

Just found a bottle of magnesium taurate in my husband's stash, looking forward to see how I do with that!

If I can't get used to either of them, I will try a bottle of the zinc gluconate drops.

Thank you, @Gondwanaland, my brain feels fried today and I needed some help.

I had forgotten I tried Zn Carnosine as well (Stomazinc) and it is very unhelpful that carnosine breaks down into alanine and histamine....

Not sure if starting with magnesium will be helpful, in my case taking Zn successfully was essential to unlock B6 metabolism and then be able to take magnesium again.

 

[Gondwanaland]

I never figured out why picolinate was so bad

https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2012.08551.x