forget it

This is for hypothesis and even educated speculation.
cdraham
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forget it

Unread post by cdraham »

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bigpoppa10040
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

Unread post by bigpoppa10040 »

I completely agree and many more people should view this thread seriously
MindChanger
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

Unread post by MindChanger »

I wrote about cytokine & serotonin connection a long time ago, and you are not right here.

The problem is not in IL-6, the problem is related to TH2 cytokines, IDO/TDO, immune predisposition (gut dysbiosis and stress) and defective serotogenic system (including genetic mutation and epigenetic changes). I have solid arguments for this statement based on advanced extensive tests, experiments and studies, which, unfortunately, I can not share at the moment.

The only thing I want to say here is that I tested all cytokines, and my TH1 cytokines (including IL6) are perfectly in the middle of the range, while my TH2 cytokines are UNDETECTABLE (IL4, IL5).

A few of quick studies:

"Murine basophils were found to participate in the Th2 polarization by instantly secreting lots of IL-4, whereas 5-HT could downregulate this IL-4 production by basophils in vitro and in vivo."

"IL4 suppresses the serotonin production in neurons" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964913/).

"IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT)" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568381/).
`
The reason why I answer to this post is because you started researching in the right direction. The thing is that receptors are proteins and they have their own half-life. So they should fix themselves no matter what, while still a majority of people here focuses on receptors. There is usually an organic issue behind disease and disease-progression. In our case, it is an extremely complex problem with extremely rare immunological predispositions in cytokine profiles and serotogenic system due to genetic mutation, gut dysbiosis and inflammatory cascade at the moment of taking a supplement.

Lyme by itself can not cause your PSSD, but PSSD could worsen your immune system to an extent that you actually got Lyme.

There is also an extreme infinite loop of elevated serotonin on immune system. Serotonin -> dysbalance in immune system -> even more serotonin -> even more dysbalance in immune system _> ..... The most responsible receptors for this are 5HT3, 5HT2A and 5HT2B, two of which are extremely overlooked here.

IDO/TDO and their implication in PSSD deserve the post, but I'd need approximately a month to bring all material into one post. I was tested for tryptophan and sertonin levels in my blood and spinal cord, and they were elevated in both cases (There were also unique antibodies).

I'd really advice you guys to focus on gut at the moment.
cdraham
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

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MindChanger
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

Unread post by MindChanger »

I think there is a probability of IDO/TDO antibodies, but take this statement with a pinch of salt in the meantime.

All my major improvements were due to interference with serotonin levels and receptors, interactions with immune system (caught a flue after experiments with histamine, dexamethasone) and influence on gut(water fasting). All my crashes were inflammatory in nature, some of the worst were from food as well as from antibiotics. There is also an extremely high probability (I'd say almost 100%) of leaky gut with a subsequent disruption of blood-brain barrier and a significant contribution to the loop. All of this leads to some conclusions. Honestly, I can feel like my immune system switches several times per day.

FMT with water fasting is an interesting option. As for metergoline and forskolin, I do not think that it can have a significant impact. Some herbs, amino acids and probiotics should be considered for fixing intensional permeability, fighting againts harmful bacteria and improving good bacteria.
cdraham
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

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MindChanger
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

Unread post by MindChanger »

Your kynurenine acid and Quinolinic acid correspond to my results.

If we talk shortly about IDO/TDO and serotonin metabolism, here is a brief description of my thoughts.

1-2% of tryptophan is converted into 5HTP through tryptophan hydroxylase, which is then converted into serotonin through aromatic L-amino-acid decarboxylase.
95% is broken down into kynurenine through IDO and TDO. The primary purpose of IDO/TDO pathway is to produce niacin and NAD.

If we talk about inflammatory predisposition (genetic, viral or bacterial), it would enhance(upregulate) IDO and TDO activity through IFN-gamma (AA->COX-2->PGE2->INF-gamma->IDO and TDO) and JNK (AA->COX-2->PGE2->JNK->IDO and TDO). It was the thing that lead you to start taking SSRIs(anxiety, depression from neuroinflammation).

Kynurenine has two pathways:
1. Kynurenine ->Quinolinic Acid -> NAD through KMO. Quinolinic Acid is a very powerful NMDA agonist
2. Kynurenine -> Kynurenic acid. Kynurenic acid is an NMDA antagonist.

When immune cells in brain (microglia) detect the virus or excessive inflammation (NMDA signaling), they downregulate KMO in order to increase Kynurenic acid or begin to produce antibodies against it or they begin to produce antibodies against NMDA receptor.

All of those lead assentially to increased NMDA inhibition through Kynurenic acid and a blockade in the production of Quinolinic Acid. If there is no Quinolinic Acid -> there is no NAD which the main goal of Kynurenine pathway. NAD takes an important part in ATP production (glycolysis) when it is used as cofactor to convert Glyceraldehyde 3-phospate into 1,3-Bisphosphoglycerate. If there is no NAD, there is no ATP (NAD is created from Quinolinic Acid and niacin). Without ATP, you end up with a lot of symptoms like fatigue. That would also lead to increased production of Kynurenic acid (NMDA inhibitor) and serotonin. It is the opposite to the proposed theory of depression where quinolinic acid inhibits production of serotonin (https://pubmed.ncbi.nlm.nih.gov/30335249/).

In the meantime excessive kynurenic acid blocks acetylcholine receptor, NMDA and AMPA receptors. SSRIs were shown to increase kynurenic acid with full remission of depression (https://www.sciencedirect.com/science/a ... 9119306622). Some interesting fact: Levels of neurally produced kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis (https://pubmed.ncbi.nlm.nih.gov/2559417 ... ter%20food.). Some of the members reported great results with fasting as well as me (I trialed fasting with some speical serotogenic drugs and got almost complete recovery for several days).

As levels of inflammation remain high (from serotonin, viruses, bacteria), body continues production of antibodies against NMDA receptor or KMO, as well as possibly other proteins to "protect" body.

Serotonin has a significant impact on immune system.

"HFD-EAE mice exhibited significantly higher MMP-9 activity and lower IL-4 levels than ND-EAE mice and were significantly correlated with brain 5-HT levels. In conclusion, the increased 5-HT levels in the brain significantly correlated with MMP-9 activity and IL-4 levels play an important role in the exacerbation of disease severity in HFD-EAE mice." (https://pubmed.ncbi.nlm.nih.gov/26820599/).
"IL4 regulates production of serotonin" (https://journals.plos.org/plosbiology/a ... =printable).
"IL4 suppresses the serotonin production in neurons" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964913/).
"IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT)" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568381/).
"Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-beta42 toxicity" (https://www.biorxiv.org/content/10.1101/227306v1).

Excessive inflammation would also lead to leaky gut, which would lead to a disruption of BBB, and a consequentive even more significant increase in serotonin.

I can't continue writing as I do not have a lot of time. The message of this post is to highlight importance of autoimmunity in PSSD, and how it could be brought up by SSRIs. I have a lot more information which I'd like to share, and, in fact, I will be doing that when I have time. Methylation, serotonin receptors, SERT, cAMP, cytokines, gut-brain axis, histamine as well as advanced thoughts on serotonin and IDO/TDO would be the next topics for discussion.

While you do not fix your constant inflammation (gut, viruses, bacteria), you will still be in the infinite loop.
cdraham
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

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cdraham
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Re: The reason we don't respond to any drugs, PSSD root cause IL6-SERT feedback loop

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