The Connection Of Serotonin And Bowel Movements?

[Astolfo]

Cypro wasn't the worst idea ever but it's certainly up to you since I wouldn't use it on myself anymore lol.

I'm gonna avoid from cypro just for now then. I got know a few things to try, thankfully.


Magnesium 200 mg

elemental(biglycinate,citrate,maleat) helps a bit to me, I'm having less sleep issues after taking one tablet at evenings. It doesn't decrease sedation or sleepiness, but It makes me less sleepy, enough to not to be fall asleep while studying my lessons. I guess I have explained it right?


I don't eat any type of meat. I just eat some cheese at mornings. I know this will make me deficient in protein but otherwise I can't even go to school because of bowel discomfort and noises. What do you suggest? 100-200 grams of liver at weekends, would it be enough for vitamins Bs?



As soon as I gather enough money, I'm gonna pay for B2 and P5P. I have also read the 'oxindole' topic, so I have some questions.


Do you think my problem is kynurenine deficiency or the opposite?


If massive amount of undegraded(TDO is underactive because of hypostress) Tryptophan passes the BBB, then there would be less IDO activity because of substrate inhibition. If it's true, then I have no problem with excitotoxic KP metabolites such as QUIN? Then the problem is only serotonin and tryptophan?

I don't know what did fluoxetine to my body, but I don't understand why I didn't go back to normal. There were times I have been too stressed at school, I'm talking about the early times of my disease. Even though, my anxiety got lesser and lesser. It should had been the opposite.

 

[GreekDemiGod]

If you're not getting clear benefits from aspirin I would stop it.

How would one even determine this? Can Aspirin have clear, distinguishable effects?
I take it for hair and it does seem to be beneficial, but besides this, I don't feel any different from this. (noticed I get minor bleeding in my nose from it).

 

[Terma]

Magnesium is always likely to do something. In terms of noticeable effects B2/R5P is more of a shot in the dark, though it's certainly essential for several pathways mentioned. But if it does nothing for a week or less in higher doses, it might not be worth breaking the bank for (you're not in a position to take supplements on faith alone) or just take lower doses after. I think Kyn pathway is most likely involved in your case but it's just not the only one, and there are only so many ways to influence it directly (localization: ketones to drive available Trp into the brain; BCAAs to keep them out; NADPH, R5P, B6/P5P, Mg, D-ribose to help it along; B3 to back it up and leave more tryptophan to others). It will depend on the organ and TDO vs IDO. But IDO generally is something you can lower simply by lowering inflammation, while ribose products (and iirc magnesium) that are used to convert quinolinic acid to niacin and lower that. I wouldn't based everything off substrate inhibition because that's basically the oxindole thread combined with some researcher's ME/CFS theory, and I don't see a particular reason to believe that's your main issue.

Given everything, it's a pretty good bet you need amino acids, as a basis for... everything, including your development. Some liver on weekends is a good idea to try, definitely. But in terms of aminos? I still buy individual aminos and whey powder (the big issue with whey is even I have only access to one expensive brand not loaded with fillers - poor product quality - and of course the people here don't like the amino acid composition and insulin spike). Those indole/oxindole issues - assuming you have them, as I wouldn't focus on that idea alone - would likely originate from gut problems, and fast-absorbing amino acids would be my first strategy to bypass them - coincidentally.

Protein bioavailability - but especially absorption speed - would impact you:
Influence of the Protein Digestion Rate on Protein Turnover in Young and Elderly Subjects
Sorry do not have a better reference on hand (if I find them again I'll post them, this was several years). Cheese is likely okay to eat if you tolerate it but realize it's slow-absorbing, not that high in protein, and I'd take days off it with a gut like that. There are some classic bodybuilding suggestions (Protein Bio-Availability Explained!) but they focus on overall bioavailability instead of absorption speed. Likely stomach acid and salt, digestive enzymes, taurine have some impact, or anything that impacts liver/gallbladder/bile (including amino acids themselves - which is part of why some people may need to hijack absorption with pure or fast-absorbing aminos). If you haven't, see also the huge thread: Amino Acid Supplementation For People With Poor Digestion

That said you may still have the problem afterward that due to the shifts in your system, protein utilization by various pathways has changed (for the worse). Meaning a cypro-like strategy where you consume them while stress signals are lowest or artificially ablated is a decent bet to help things along.

I've had lessening of anxiety myself over the years with development of disease. Changes in serotonin receptor sensitivity and release/reuptake, increased kynurenic acid, kappa-opioid receptor (down)regulation, hormonal changes (e.g. increased progesterone or relative ratios), increased endocannabinoid signaling, increase in muscarinic acetylcholine receptors (parasympathetic tone) and/or lowering of nicotinic receptors (sympathetic), changes in norepinephrine/epinephrine signaling, histamine, of course GABA and its receptors, and more could all be expected to do that under the right circumstances or combinations. Keep in mind the serotonin system is partially evolved specifically as a defense against energy expenditure through its ability to promote stress tolerance in non-fight-or-flight situations or energy conservation in general, and fluoxetine is somewhat designed to lower anxiety. That said I'm not exactly sure in what state fluoxetine left your system when you stopped it, given the other drug, the multiple systems involved and the guesswork, which is what most of this is

(At some point you could try adding high amounts of certain high folate-containing vegetables with different fibre quantities to see what it does to your gut - and to complement the protein and B2 - sort of like Travis did - but this is highly ymmv and didn't work out well for me)

How would one even determine this? Can Aspirin have clear, distinguishable effects?
I take it for hair and it does seem to be beneficial, but besides this, I don't feel any different from this. (noticed I get minor bleeding in my nose from it).

Yeah some you'd notice either subjectively or on hormone/labs (always a good bet), others are more subtle. It has properties of a generic COX-based anti-inflammatory after all. Most likely the healthier you are or less inflamed to begin with the less you'd notice it at the standard doses. I tried to use it on/off for a few years at 100mg-1.5g doses [can't remember if tried the 4g one, probably] but did nothing too impressive, while overuse left me feeling off. For myself didn't want to risk affecting my hearing since I've had tinnitus, I already took progesterone and caffeine which are much more obvious and stronger at lower doses, and it's unclear if salicylate issues run in my family or not, so overall it wasn't smart to take it on faith. I would not ignore nosebleeds either, but the rest of the forum has ideas on that one, not unique to aspirin. It's just a tool to me, whereas a minimum of vitamin E which is comparable is something essential. Also it annoys me Bayer came up with it.

 

[Astolfo]

Magnesium is always likely to do something. In terms of noticeable effects B2/R5P is more of a shot in the dark, though it's certainly essential for several pathways mentioned. But if it does nothing for a week or less in higher doses, it might not be worth breaking the bank for (you're not in a position to take supplements on faith alone) or just take lower doses after.

Yeah, as you said, I'm planning to take them if only I see a difference. I haven't yet bought the P5P and B2 but I will do it this month. The magnesium product I'm using has 200 mg total elemental magnesium per tablet. It's not so cheap considering it contains only the half of the RDA. But, all the oxide forms being sold here contains lots of additives like colouring agent and sweetener. Apparently I have no good option here for magnesium source.

Bananas have high amount of B6, histidine and some magnesium. Maybe I can drink some banana juice a few times a week.

I have looked for NADPH and D-ribose but they aren't available here. BCAA is being sold but it's 130 TL. That's a lot for an amino acid which I'm not sure have any effect at all.

Protein doesn't directly cause gut problems. I have lots of bowel discomfort and noise at "nights". Some days, I can't even sleep because of bloating and movements happening at my bowel. These problems occurs mostly after 12 or 1 pm. Also I get a strange diuretic effect at nights. But that diuretic effects is not new, It was happening before too.

I want to add one symptoms to my list. Actually it started several months ago but the summer just ended here, so it appeared again. I'm gonna give the example from yesterday. Yesterday night, I woke up at 6 am with massive amount of bowel discomfort and freezing. My body can't regulate temperature anymore I guess. I'm having freeze even at about 20 degrees. Somehow, thermoregulation of my body is messed up too.

The hungriness became so much problem lately. I'm starving food most of the times. I'm eating more than ever, and I don't even have appetite but nevertheless I'm always starving food. I was 59 Kg a few months ago and I'm now 62. Fat accumulation on my stomach area is significant also.
I don't think I'm being overly dramatic, I'm gonna really become an obese if I can't stop this.

Sticking to only one theory is not right, but it's the only theory that explains both neurological and metabolic problems I have. I only have to learn what keep GR receptors inbalanced at this point.

Maybe 5HT7?

Glucocorticoid receptor expression in primary hippocampal cell cultures was significantly increased with either 10 mM 8-bromo cAMP, 50 nM 5-carboxamidotryptamine (5-CT), a potent 5-HT7 receptor agonist, or 100 nM 5-HT. The effect of 5-HT or 5-CT was blocked with methiothepin or by a protein kinase A inhibitor, but not pindolol. These results suggest that the effects of 5-HT on hippocampal GR expression is mediated by a 5-HT7 receptor.

By any chance, do you know any way to break the metabolic trap in underexpressed IDO?(substrate inhibition). Maybe if I can push IDO1 temporarly, everything may turn back to normal including serotonin and GR.

Also one more question. If I feel better when I'm starving food, is that mean I feel better when the TRP level increases in my brain? Doesn't it conflict with what I said above?

 

[Terma]

NADPH isn't a supplement, sorry. I meant anything that increases NADPH. I listed some elsewhere: methylfolate, glutathione precursors glutamine+glycine+NAC (note: also promoted by whey powder) as this can spare NADPH in sick people, potentially malic acid if deliverable to cells, ...

BCAA alone would probably not go that far for you, but you could find they have diagnostic value. You could try buying a small amount, but just enough for 5-6 higher doses of BCAAs for a couple days. It might give you some hint on where your tryptophan really needs to be. Keep some carbs around, and it would be idea to get some L-tyrosine to avoid lowering dopamine at the same time.

Iirc bananas contain serotonin. I tried eating tons of them years ago and weird things happened. Not sure how much carries over into the juice though.

Gut problems like that are from high serotonin and/or high gut flora activity and immune activity (often all happen together) or alternatively from an overactive sympathetic system (epinephrine, nicotinic acetylcholine receptors). I have years of problems of that sort that were temporarily but very usefully improved by 5-HT3 antagonists (tetrahydrocannibiol, possibly adamantane, maybe oral DHEA or even topical but I'm not sure and alone it doesn't always work on me nor strongly; clinically they give you ondansetron) and opiates (loperamide, available over-the-counter in North America - but you do develop a tolerance - for occasional use only; even tianeptine worked for this but I don't recommend it to you). I also have had frequent urination for years - that one is harder and as yerrag wrote recently that could be tied to LPS/endotoxin from the gut, realistically.

Hypothermia can be from gut LPS/endotoxin (Effects of Hypothermia on Mortality and Inflammatory Responses to Endotoxin-Induced Shock in Rats) and also serotonin (except I don't remember if that is more affected by central or peripheral serotonin). Acetylcholine changes also, possibly. And other stuff you surely know if you read this forum at all.

5-HT7 is involved in the circadian rhythm and can be modulated in a complex way by oleamide (https://www.ncbi.nlm.nih.gov/pubmed/9928256; search Travis's post history for that one). Its antagonists can be used as antidepressants or antipsychotics (amisulpride), but I imagine also as circadian rhythm modulators (can't remember what did that). That receptor does have value in circadian rhythm and most likely yours was affected as well. However, note that 5-HT7 activation lowers body temperature (No hypothermic response to serotonin in 5-HT7 receptor knockout mice).

You generally do not want to push IDO unless you specifically have Dr. Phair's theoretical condition. If it's only indoles/oxindoles that explained that idea and you don't have a defective enzyme (for whatever reason), then generally the high levels of intracellular tryptophan in IDO-expressing cells would resolve themselves (not clear on the kinetics of this idea so can't give a number, would need help on that one). You want to normalize IDO, e.g. by restoring circadian rhythm as that helps restore normalcy and cycling of the immune system.

Hunger comes from ghrelin, leptin and such, sometimes associated with serotonin one way or the other - depending on the predominant receptor activation, signal strengh and timeframe - but predominantly reported as suppressing apetite ([Serotonin and hypothalamic control of hunger: a review]. - PubMed - NCBI). They aren't the only factor (GH/IGF-1, insulin, etc.) but amino acids are important in satiety, as can be carbs. It's not likely cypro would have helped that, but then again ymmv. Of course this can be related to blood sugar control in general, and so by proxy indication of liver, pancreas and other organ function.

Don't forget: glucocorticoids are extremely tied to the circadian rhythm, meaning that 5-HT7 GR remark seems in line with 5-HT7's known effects on sleep and hypothermia.

 

[Terma]

As a summary this doesn't seem too bad:
5-HT7 receptor - Wikipedia

When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein Gs from the GPCR complex. Gs in turn activates adenylate cyclase which increases intracellular levels of the second messenger cAMP.

The 5-HT7 receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract.[5] The highest 5-HT7 receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.[10][11]

 

[Amazoniac]

I would not waste money on a single B-vitamin, it's preferable to invest on antidote C in this case.

There might be a treshold for imported goods where you isn't taxed if the price is lower; can be too expensive for the government to pay an employee to inspect every insignificant package in details.

Let's say that you buy B-vitamins from bulk vendors. It will cost around U$50 + inexpensive shipping. If each bag contains 25 g and you consume 50 mg/d, you have enough of it for 500 days, which is insane, you'll be a grandpa with your pet supplements. In reality they will likely spoil earlier than you can use them, which is why dividing with a friend the supplement and costs is a solution; or involve more people while going for economic options, for example 50 g of each divided by 3 people, the PPP (price per pimp) drops considerably.

Not eating meat and favoring casein is common here. You must have friends that are into bodybuilding who supplement creatine, maybe you can try some with it and magnesium?

The point is that there must be viable alternatives that are going to be superior and save you money in the long-run.


You have a B-complex, right? Which one? Have you tried to hydrate it to a paste and apply topically? You should be able to reduce the chances of absorbing the titanium dioxide by creating local competition in placing together other minerals (small amounts of magnesium, etc) on the region.

Someone posted about using a coffee filter to retain problematic stuff from supplements. This can be related to the Turkish coffee: bean syndrome. However, it's safer to stick to transdermal supplementation for now.

It is food market is with fortified items, such as energy is drinks? Perhaps it's an acceptable trade-off.


It can be challenging to know for certainty the specific pathways that got screwed and the priority in addressing them. The drug was used for a reason, so you was already dealing with issues. It's simpler to assume that the body will take care of it if you provide enough usable nutrition.

I would leave dietary choices for intuition and obtain whatever's missing through supplements, it's messed up to confuse your senses and rarely ends well.
How is your nutrition like? Is there anything you crave but can't eat? How being hungry with no appetite works? These are the primary questions that will give you a clearer picture for a starting place and clues on what has to be done.


- Th1/Th2 Balance: The Hypothesis, its Limitations, and Implications for Health and Disease


If I don't reply, it's not because of your skin color, it's due to not having anything practical to add.

 

[Astolfo]

BCAA alone would probably not go that far for you, but you could find they have diagnostic value. You could try buying a small amount, but just enough for 5-6 higher doses of BCAAs for a couple days. It might give you some hint on where your tryptophan really needs to be. Keep some carbs around, and it would be idea to get some L-tyrosine to avoid lowering dopamine at the same time.

Thanks for the suggestion. It's good to know that BCAA keeps the tryptophan in the body away from brain.

and opiates (loperamide, available over-the-counter in North America - but you do develop a tolerance - for occasional use only;

Yeah, I used it several months ago for school exams. It really helped me.


I must add this. All the metabolic snydrome effects started after my cyproheptadine crash. 4 mg At one night, severe hypoglycemia symptoms and since that day, I'm having extreme craving for food, very regularly. Also gaining weight.

https://www.researchgate.net/public...ood_lymphocytes.pdf?origin=publication_detail

Maybe this aspect of my disease is not caused by antidepressant at all.

CONCLUSION: The current study showed that cyproheptadine HCl may have unwanted side effects, and its abuse may lead to disturbances in white blood cell especially lymphocyte which in turn will affect the immunity of persons taking it, especially in children, since the immune system modulates ILs secretion to face the irritability of drug behavior, that will lead abnormalities in human immune system.

Obesity, on the other hand, is one of the main risk factors of noncommunicable diseases worldwide, especially in Iraq.[15] The use of cyproheptadine to increase body weight may lead to the risk of becoming obese.[16]

It's so frustrating. On top of CFS, I got this from cypro, and got permanent tinnitus after aspirin. Saw palmetto was a dumb choice but it caused slight gyno too.

Could Downregulated 5HT1A receptors cause high 5HT7 activity?

I had a major interest in the serotonin pathways before I came to this forum. I know 5ht1a has shown benefits for schizophrenics (as has 5ht7 antagonism).

Here is my old post from pssdforum. Nov 02 2018.

"I had a sudden worsening after eating 2 grams of black pepper with 3-4 grams turmeric. I haven't seen any improvement after that day."


Could that because it inhibits IDO? Yesterday I read some posts on phoenixrising. Took some screenshots:

 

[Terma]

Sure that's interesting. For the moment you could read Travis's history since he talked about the AhR. I haven't put as much focus on it, a bit since any of the KP enzymes can also go wrong leading to Trp backup and that affects both TDO and IDO, and TDO is the major Trp consumer leaving IDO as a more specific type of (immune) cell dysfunction. But I suppose other indoles formed by gut bacteria might impede AhR signaling further or disproportionately. Yet many things will: Aryl hydrocarbon receptor - Wikipedia

Research has focused on naturally occurring compounds with the hope of identifying an endogenous ligand. Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of tryptophan such as indigo dye and indirubin,[17] tetrapyrroles such as bilirubin,[18] the arachidonic acid metabolites lipoxin A4 and prostaglandin G,[19] modified low-density lipoprotein[20] and several dietary carotenoids.[16] One assumption made in the search for an endogenous ligand is that the ligand will be a receptor agonist. However, work by Savouret et al. has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.[21]

The only part that irks me is Phair's comment about tryptophan causing issues for ME/CFS people, because some of them benefitted from whey powder. Although it contains BCAAs, alpha-lactalbumin, lysine, methionine and can increase glutathione (sparing NADPH + more), if tryptophan is truly at the root of everything it's hard to imagine quantitatively how dietary tryptophan contributing to intracellular overload in IDO-expressing cells could be the most significant culprit since whey is a good source of tryptophan (rather it suggests maybe more that the dietary tryptophan is missing cofactors such as NADPH, or almost an expression of amino acid imbalance, which can occur at many levels and disorders, or their incorrect localization, or utilization) [Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers. - PubMed - NCBI - Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cogn... - PubMed - NCBI]. Of course these observations about beneficial effects of whey have an anecdotal aspect to them and patient categorization problems, but it goes so far as to some people benefiting from L-tryptophan supplements alone if you look around. Localization (organ, body vs brain) of the problematic IDO-expressing cells would also be a factor. (I don't discount his idea but I question the likelihood or rather frequency; or otherwise there is some other important factor involved such as brain vs body, cell types or other KP enzymes; or more generally a collection of 2 or more disease-modifying aspects, which might involve brain vs body or other localization, together with cell type specificity for IDO and/or TDO, e.g.: IDO-only cells might get worsened by dietary tryptophan flux while TDO-expressing cells, or in other words maybe the immune system suffers while the liver if not too inflamed or parts of the brain can benefit from it?)

In a way you can see tryptophan as beneficial to liver and brain (for NAD+, KYNA, maybe other synthesis) but only as long as inflammation or gut-originating disturbances to that organ are also low. The same picture might emerge pitting cell types against one another. In the worst case, you might benefit those areas while worsening something immune-related. I could see in that case how whey or high tryptophan containing foods might become problematic. But that rides on quite a few unquantified variables and some combination of anomalous factors (indoles/oxindole and/or AhR ligands, genetics, immune activity and inflammation in general). (Personally, I got rid of my ME/CFS-like symptoms and consumed tons of protein - more than most people - notably whey, even poor quality - frequently... in other words, his ideas suggest to me a mechanism for sub-cases of disease severity more than one unifying cause... but that's only my guess)

If I had to place a bet, it would be on indoles/oxindoles or other AhR receptor agonists (in particuliar compounds formed by gut bacteria or as a result of other organ dysfunction) as causing IDO inhibition rather than the kinetics of the IDO enzymes alone, but that is my guess and it is sure Phair studied some aspects I haven't - but there are a lot of possible causes and contributing factors here (notably the other KP cofactors and enzymes).

I was not aware you had a cyproheptadine crash - or rather I didn't interpret that as a "crash". Well, interesting...

 

[Terma]

I found this interesting:
IDO, COX and iNOS have an important role in the proliferation of Neospora caninum in neuron/glia co-cultures. - PubMed - NCBI

Central nervous system (CNS) is the main site for encystment of Neospora caninum in different animal species. In this tissue, glial cells (astrocytes and microglia) modulate responses to aggression in order to preserve homeostasis and neuronal function. Previous data showed that when primary cultures of glial cells are infected with N. caninum, they develop gliosis and the immune response is characterized by the release of TNF and IL-10, followed by the control of parasite proliferation. In order to elucidate this control, three enzymatic systems involved in parasite-versus-host interactions were observed on a model of neuron/glia co/cultures obtained from rat brains. Indoleamine 2,3-dioxygenase (IDO), induced nitric oxide synthase (iNOS) responsible for the catabolism of tryptophan and arginine, respectively, and cycloxigenase (COX) were studied comparing their modulation by respective inhibitors with the number of tachyzoites or the immune response measured by the release of IL-10 and TNF. Cells were treated with the inhibitors of iNOS (1.5 mM L-NAME), IDO (1 mM 1-methyl tryptophan), COX-1 (1 μM indomethacin) and COX-2 (1 μM nimesulide) before infection with tachyzoites of N. caninum (1:1 cell: parasite). After 72 h of infection, immunocytochemistry showed astrogliosis and a significant increase in the number and length of neurites, compared with uninfected co-cultures, while an increase of IL-10 and TNF was verified. N. caninum did not change iNOS activity, but the inhibition of the basal levels of this enzyme stimulated parasite proliferation. Additionally, a significant increase of about 40% was verified in the IDO activity, whose inhibition caused 1.2-fold increase in parasitic growth. For COX-2 activity, infection of cultures stimulated a significant increase in release of PGE2 and its inhibition by nimesulide allowed the parasitic growth. These data indicate that iNOS, IDO and COX-2 control the proliferation of N. caninum in this in vitro model. On the other hand, the release of IL-10 by glia besides modulating the inflammation also allow the continuity of parasitism.

The bolded part suggests either the classical theory of bacteria/parasite tryptophan starvation (as Travis and I argued about) or alternatively the kynurenine metabolites (such as anthranilic acid derivatives) are anti-pathogenic themselves or yet they have specific immune-modifying aspects, possibly such as modifying the activation of innate vs adaptive immunity.

It shows also the involvement of COX, iNOS, PGE2 in danger signaling and suggests consequences for ablating them too much or in the wrong circumstances.

Interesting note:

The tryptophan pathways triggered by IDO is described as a potent antiparasitic mechanism (Heseler et al., 2008; Murakami et al., 2012) and this enzyme, which activation contributes to CNS homeostasis, is expressed by brain cells including microglia and astrocytes (Guillemin et al., 2001).

Rozenfeld et al. (2003) observed that the immune response triggered by T. gondii mediated by PGE 2 and IL-10 was responsible for the reduction of the nitric oxide synthesis, supporting the concept that T. gondii reduces inflammation for neuronal preservation.

(I suspected I might have chronic infection from this parasite in the brain, though that's far from clear; however:)

Additionally, the lack of IFNy and nitric oxide corresponded to a gain in tissue preservation, by the reduction of the deleterious effects of these inflammatory mediators on the microenvironment, as it was described (Gresa - Arribas et al., 2012; Jesus et al., 2013).

After the initial step of tryptophan pathway catalyzed by IDO, the kynurenine has two distinct branches: one of them responsible for the production of quinolinic acid (QUIN) and the other branch regulated by kynurenine aminotransferase (KAT), which produces kynurenic acid (KYNA). QUIN is described as an agonist of NMDA receptors while KYNA is its antagonist (Fugigaki et al., 2017). In CNS cells, QUIN is usually released by the activation of microglia (Alberati - Giani et al., 1996; Heys et al., 1996) while astrocytes predominantly express the isoenzyme KAT II to produce KYNA (Guillemin et al . , 1999). N. caninum infection could contribute to the preservation of the tissue by the activation of the KAT branch prior to the one related to neurotoxicity during the glia activation.

We observed that infection with N. caninum induced the release of PGE2 and also that parasitic proliferation occurred by the inhibition of both isoenzymes COX-1 and COX-2, confirming that this prostanoid also participates in this parasite control. A down regulation of iNOS could also be associated with the presence of PGE2 in infected cultures. Some studies have demonstrated the inhibitory effect of PGE2 in the synthesis of nitric oxide to prevent the deleterious effects of an exacerbated inflammatory process (Minghetti et al., 1997; D'acquisto et al., 1998; Kobayashi et al., 2001; Boje et al., 2003). According to our data, a synergistic effect between IL-10 and PGE2 is likely to contribute to the homeostasis of the microenvironment, by reversing pro-inflammatory conditions. It has been observed that the interaction between PGE2 and both its receptors, EP4 and EP2, promotes anti-inflammatory effects and neuroprotection (Echeverria et al., 2005; Shi et al., 2010).

Altogether, the data suggest some interpretations such as: (1) the parasitic growth was controlled by enzymatic activity of IDO and COX-2 while basal level of iNOS could contribute in this control; (2) the regulatory effects of IL-10 and PGE2 are able to modulate inflammatory processes and maintain the homeostasis of the microenvironment. Further studies are needed to clarify some questions specially related to the protection of the tissue attributed to tryptophan catabolites in CNS cells by N. caninum.

(These help summarize a bunch of concepts I don't feel like describing)

 

[Terma]

I guess you could reason: if cyproheptadine lowered IL-10 as you posted [https://www.researchgate.net/public...ood_lymphocytes.pdf?origin=publication_detail], it would appear to increase types of immune activity. This would have the same (well, it seems worse) effect on IL-10 as loss of GR sensitivity or glucocorticoids or their antagonism [Glucocorticoids up-regulate constitutive interleukin-10 production by human monocytes. - PubMed - NCBI].

See also: Differential Regulation of Interleukin-10 (IL-10) and IL-12 by Glucocorticoids In Vitro

With regard to IL-10 we observed in various donors stimulation by GC rather than an inhibitory effect. That this was not a consistent finding in all donors may be due to the fact that in most of the donors occupancy of the GR has already occurred by endogenous cortisol and, consequently, that positive regulation of IL-10 has already been achieved; such a condition will probably be present in the majority of the donors because the whole-blood cultures were performed in the presence of autologous plasma. Preliminary data indicate that stimulation of IL-10 by low concentrations of cortisol is found more frequently using cultures of isolated PBMC. A stimulatory role for GC was in particular evident from the fact that the GR antagonist RU486 inhibited IL-10. This appeared not to be a nonspecific effect because IL-12(p40) and IL-12(p70) were stimulated. Because RU486 may act as an agonist for the progesterone receptor, 31 we ruled out that progesterone had inhibitory effects on IL-10 or stimulatory effects on IL-12 (data not shown).

 

[Astolfo]

There might be a treshold for imported goods where you isn't taxed if the price is lower; can be too expensive for the government to pay an employee to inspect every insignificant package in details.

That treshold is now 0 TL. A few months ago, governement decided to start taking tax from everything bought from abroad. Lots of tax and the huge difference in exchange rates is a problem

Not eating meat and favoring casein is common here. You must have friends that are into bodybuilding who supplement creatine, maybe you can try some with it and magnesium?

I have asperger's. I don't have any friends. Nobody I know is into the bodybuilding either.

You have a B-complex, right? Which one? Have you tried to hydrate it to a paste and apply topically? You should be able to reduce the chances of absorbing the titanium dioxide by creating local competition in placing together other minerals (small amounts of magnesium, etc) on the region.

Nutraxine

I'm going to try taking it topically, although I didn't even succeed to solve it into water. It has very solid tablets.

For the moment you could read Travis's history since he talked about the AhR.

I couldn't search Travis' posts?

The only part that irks me is Phair's comment about tryptophan causing issues for ME/CFS people, because some of them benefitted from whey powder. Although it contains BCAAs, alpha-lactalbumin, lysine, methionine and can increase glutathione (sparing NADPH + more), if tryptophan is truly at the root of everything it's hard to imagine quantitatively how dietary tryptophan contributing to intracellular overload in IDO-expressing cells could be the most significant culprit since whey is a good source of tryptophan (rather it suggests maybe more that the dietary tryptophan is missing cofactors such as NADPH, or almost an expression of amino acid imbalance, which can occur at many levels and disorders, or their incorrect localization, or utilization) [Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers. - PubMed - NCBI - Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cogn... - PubMed - NCBI]. Of course these observations about beneficial effects of whey have an anecdotal aspect to them and patient categorization problems, but it goes so far as to some people benefiting from L-tryptophan supplements alone if you look around. Localization (organ, body vs brain) of the problematic IDO-expressing cells would also be a factor. (I don't discount his idea but I question the likelihood or rather frequency; or otherwise there is some other important factor involved such as brain vs body, cell types or other KP enzymes; or more generally a collection of 2 or more disease-modifying aspects, which might involve brain vs body or other localization, together with cell type specificity for IDO and/or TDO, e.g.: IDO-only cells might get worsened by dietary tryptophan flux while TDO-expressing cells, or in other words maybe the immune system suffers while the liver if not too inflamed or parts of the brain can benefit from it?)

In a way you can see tryptophan as beneficial to liver and brain (for NAD+, KYNA, maybe other synthesis) but only as long as inflammation or gut-originating disturbances to that organ are also low. The same picture might emerge pitting cell types against one another. In the worst case, you might benefit those areas while worsening something immune-related. I could see in that case how whey or high tryptophan containing foods might become problematic. But that rides on quite a few unquantified variables and some combination of anomalous factors (indoles/oxindole and/or AhR ligands, genetics, immune activity and inflammation in general). (Personally, I got rid of my ME/CFS-like symptoms and consumed tons of protein - more than most people - notably whey, even poor quality - frequently... in other words, his ideas suggest to me a mechanism for sub-cases of disease severity more than one unifying cause... but that's only my guess)

If I had to place a bet, it would be on indoles/oxindoles or other AhR receptor agonists (in particuliar compounds formed by gut bacteria or as a result of other organ dysfunction) as causing IDO inhibition rather than the kinetics of the IDO enzymes alone, but that is my guess and it is sure Phair studied some aspects I haven't - but there are a lot of possible causes and contributing factors here (notably the other KP cofactors and enzymes).

I understand. Do you have any idea how to fix that bacterial issue?


Also, I have to find a way to fix hypothermia. I couldn't sleep today. When I'm sleep deprived, all my gut problems increase. It's really hard to even stay in class while there is tons of gas and movement in the bowel. It's not only a gas problem though, when I go to bathroom, I can't do anything about it. Everything happens in the class, when there is a cognitive stimuli.

I don't know, maybe sympatethic/parasympathetic balance have been disturbed cuz GRs.

 

[Terma]

Yeah, I feel you, I've had those gut problems, it really messes with your life. Clearly it interacts with the circadian rhythm and neurotransmitters but it's kind of hard to wrap your head around. All the circadian-dependent processes (which is a lot of things) including the gut and the immune system have to align. Not to mention: 5-HT2c, 5-HT7, cortisol, hypothalamus, liver, NAD+/NADH (NADPH), methylation, steroid synthesis...

His username was simply "Travis". The forum doesn't have him in the active user list anymore or some ***t I forget so you have to input it manually. Thankfully he picked an easy name for us to remember him by.

 

[Astolfo]

I see. Now reading all kynurenine related posts from Travis.

I have and still been sick for 3 days. Runny nose, very mild pain in throat etc.

The illness made my gut problems a lot worse, even in absence of protein. So, I had been taking loperamide(10mg) for 2 days. That completely abolishes my gut problem.

But today, my right thumb started twitching. I'd like to point out that, I don't have myoclonus right now. So, this is a different thing.




It's been twitchig like that, since 3 hours.

I noticed that what triggers that is same as what triggers my gut. When there is a cognitive/stress stimuli, my thumb twitches a lot. It's haven't stopped yet btw.


Your posts really helped me thinking different situations about IDO, but nevertheless I guess I don't have any clue.
Upregulated IDO, saturated/downregulated KMO which caused by depletion of NADPH makes sense. But all the studies I have looked so far concludes on "high QUIN, excitotoxicity, neurological damage, anxiety."

If I got less anxious over time, is that means I have the opposite (low quin, K, high tryptophan/serotonin)? Or is that means QUIN have destroyed lots of neurons and it made me dumber and less anxious?

https://www.researchgate.net/public...ed_Toward_Kynurenine_Monooxygenase_Activation

This study says obesity == high KP metabolites and high KMO

Actually, IDO-1-mediated tryptophan catabolism due to chronic immune activation is the cause of reduced tryptophan plasma levels and be considered as the driving force for food intake in morbidly obese patients. Thus, decrease in plasma tryptophan levels and subsequent reduction in serotonin (5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity.

The Interactions Between Kynurenine, Folate, Methionine and Pteridine Pathways in Obesity. - PubMed - NCBI

This study says, high Immune activity, increased IDO == obesity, food craving(low serotonin), low tryptophan.

I thought IDO knocks out the immune system?


Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression. - PubMed - NCBI

This study says GR insensitivity == low kynurenine/tryptophan


By the way, I don't get the same sedating effect from cheese, despite that it has much more tryptophan content than meat. I'm eating cheese and white bread every morning for a weeks and It doesn't aggreviate my gut symptoms either.

 

[Astolfo]

@Terma forgot to mention again.

 

[Terma]

You don't have to @ me, the forum tells me anyway :P

Kynurenine metabolites or activation of IDO is often associated with relative lowered immune activity because of the combination of some of those metabolites being immunosuppressive (e.g. xanthurenic acid) and because tryptophan is used by both the immune system and (though the important of this part is debated, Travis didn't agree) by pathogens. But this depends where the metabolite bottleneck is, because kynurenine itself is a sort of half-tryptophan in terms of mTor agonism on T-cells and other cells - so NADPH depletion produces a different effect. It's hard to say what the overall effect will be, just from this pathway alone, and then you have to factor in all the others and circumstances.

In obesity they've thought for awhile macrophages are involved, but it won't necessarily translate well to other tissues or issues. Generally it is just ascribed to adipocyte inflammation + macrophage infiltration, which always ends up increasing IDO through one cytokine/mechanism or other. They're not talking about the immune activity in the rest of the system on that topic usually.

In the CHD study I figure the loss of GR and other issues leads to higher inflammation, and the kynurenine pathway tries to compensate for it but cannot in that case (CHD+depression, sounds like fun). Loss of GR will probably also lower TDO in the liver, leaving more Trp available for IDO and serotonin in the body (but it seems like they do compensate at least for the Trp levels since it lowered in serum, though intracellular is possibly another story) - away from NAD+. Then the circadian rhythm eventually goes. [Note: afaik they didn't measure anything in the CNS, and this is further complicated by the blood-brain barrier if talking about depression, so this analysis is inherently incomplete - salt to taste]

Yeah casein is indeed a slow-digesting protein. It also won't affect the same bacteria as meat. This is impossible to quantify for you, though. Your cheese might also be higher in fat, which can help gut sometimes and slow down digestion (vinegar would further modulate this). You can always mess around with different types of fats, though not likely to help the waistline (cheese never helped mine). [Note: these foods are all "ymmv" due to gut flora]

I'm a little too tired to connect things further at the moment. I've had those twitches but I honestly never paid that much attention to it since it never lasted.

 

[Terma]

He's the picture from your folate article, it's not bad so might as well:

Anyway the problems with folate come down to DHFR (NADPH, but also NADH apparently?), SHMT (B6, serine) and its isoforms, plus its binding proteins/receptors for cellular uptake (see Travis posts for that). Other than some link to NADPH oxidase I haven't read, their link to folate is pretty predictable so not much to say. Nice to them to include BH4 somewhere (although DHFR can regenerate it, the link to supplemental forms of folate was never perfectly clear). Essentially these things are supported by methylfolate (in reality methylene-tetrahydrofolate) though it needs a lot of cofactors to work perpetually.

 

[Astolfo]

I'm a little too tired to connect things further at the moment. I've had those twitches but I honestly never paid that much attention to it since it never lasted.

Thanfully it stopped. Maybe it was because I was sicker yesterday, or cuz from loperamide, and maybe both.


I have a weird question in my mind:

From the psychological aspect, What's the consequences of High KYNA and High QUIN? One of them is neuroprotective/sedator at high dosages and the other one is excitatory/neurotoxic.

Is it possible I got and still getting excitatoxic brain damage 'while absence of anxiety'? I haven't read posts on PR forum but it appears that they have anxiety problem. What if I have low GR sensitivity, high QUIN and KYNA as I said? Low immune activity, high trp availability, constant inflammation, high IDO(compensating mechanism), that's how it works as far as I understand from your post. I have read other possibilities but I need to start to try breaking this chain and I want to start by the easiest theory.

If I don't see any window/remission, is that essentialy means what have I got is untreatable? These days, I really feel like a completely different person. I don't remember how it felt like being in my school with my friends, talking with my closest friend(that's the biggest thing makes me very uncomfortable) etc. I feel like a complete newborn to everything.

Could you recommend me anything for breaking the chain? I guess I should look into what keeps my adrenals in that state. I'm going to try finding some articles about how fluoxetine affects GRs, so maybe I could get a clue.

 

[Terma]

Well high KYNA following high QUIN is predictable to happen. That will be a balance between activities of astrocytes and microglia. Some things even increase astrocyte populations, and so simply the number of cells of each type could be one way persistent changes happen (just one example). It is manifested in a range of conditions so high QUIN isn't very deterministic of outcome and is a generic feature of microglial activation. The KP seems somewhat primitive compared to the serotonin system so it is less specific.

Anyway it is rarely permanent damage but rather a balance between insults and healing. This is where the value of the circadian rhythm comes into play: if you don't sleep properly or get enough protein, you are less likely to heal from insults such as those from excess QUIN. If you consider cyproheptadine, you can see it as an emulator of sleep for healing purposes. I am pretty sure I've had tons of high levels of QUIN over the years, but per se it doesn't drive my decisions of what to take much other than what I mentioned. It's one marker and an easy target for researchers because they all know it already.

The fact you are able to follow a good part of this at 17 years old suggests you've preserved (or developed some forms of) intelligence and the changes are more transient in nature. You don't get enough credit, because I never would have been able to follow this stuff at 17. I do suspect the serotonin system would be involved for you as well as the GR, but the serotonin system is one of the things that helped humans survive.

It will affect your reward system, and I can relate to personality changes in dramatic ways I can't even describe on this forum without alienating the world. It's definitely not "untreatable", otherwise I wouldn't be talking to you. It becomes an inferior alternate state of homeostatis your body falls into, at the expense of one or more cell populations or organs such as the gut or liver, the latter which is designed to take a beating for the other organs (yours probably has quite a ways to go, though you should still get it tested the day you get a chance, to be safe). Yes it might need a strong nudge somewhere - or alternatively/combined with an extended period of rest and nutrition (e.g. in older medicine they used to keep people chained to beds for extended periods and feed them nothing but raw milk - you're still going to school and stuff I gather) - which is why I don't look down on cyproheptadine in principle and I gravitate toward stronger solutions myself, albeit often they have been temporary (but still of major value). It is mostly because of your limited access to things that I don't know what else to suggest, and I cannot in good conscience suggest things I have no experience with or I would have hesitated to take at 17. At this point everything I know is in my post history.

You could try diphenhydramine instead of cypro but I did poorly on that one and it's not a superb drug - antihistamines are not a terrible bet, though I highly suspect they do not work best alone but simply open a door to healing. Again, personally caffeine distorted my system and seemed to keep it in a state of sympathetic activation, as useful as it was. It has pro-metabolic abilities but it does more than that and does not help rest/healing much when you're not well, as it will distort acetylcholine, adrenergic, histaminergic and of course purinergic (adenosine) signaling - chronic caffeine itself puts you in an alternate state of homeostatis. It can have anti-inflammatory effects but that does not make it appropriate either (rather it may be an indication for finding something else less of a blunt weapon). Furthermore coffee contains tons of other compounds that could theoretically be tried in isolation. Meanwhile there are several major GABA agonists and other inhibitory substances that can be used to improve rest at least temporarily but significantly (typically things you don't want to take on a daily basis, but on a few times a week basis). Several of them (all in my post history somewhere) however can have major dependency problems and abuse potential, so I really don't know if you should go there. [Don't forget basics like gelatin either if you can find some in a food market - didn't solve much for me but is definitely worth a shot - though keep in mind especially at your age its amino acid profile must be balanced out by other protein sources]

In the absence of a specific understanding of your physiology and the circumstances, if I were you I would focus on attaining rest with whatever means available at your disposal. These things I write are the limits of my incomplete knowledge on these matters - they are supposed to give you the idea that this isn't hopeless but that it might take you and your body some time to address, and possibly you need better diagnostics from somewhere and expertise on whatever they bring to light. The very worst case is simply that you have to wait for more research to happen, but the pace of research is unrivaled in history and you will outlive me to see even more of it. Alternatively, you might have to visit another country. This doesn't mean there might not be a faster way out either, but I don't know what it is or who could tell you given circumstances. There's always hope for these cases, just needs more information and diagnostics somehow (and some experimentation).

 

[Astolfo]

I understand. Anyway, your posts really helped me.

Personally, I decided to not to take cyproheptadine. That was a bad trial all in all.

A few days ago I have seen a topic on hackstasis. That was very helpful. What I had read is not news to me, but I just associated adrenals and serotonin system better in my mind.

Upregulated GR( cortisol) receptor theory

Area1255's new theory to PSSD cure

Especially today, it was so hard to stay in school because of my bowel. I had really hard times even though I took 10 mg loperamide this morning. I made a mistake by masturbating yesterday night right after drinking coffee. Panic attack, heart wrenching, I got crashed a bit.

I think If I can heal my adrenals, all that
Tryptophan, serotonin, kynurenine, etc. Problems will be resolve, at least primarly.

I don't have the extract, but I have licorice root sticks. I will make one cup of tea a day with 10 gram of slice. My biggest concern is it may fail because lack of anti-serotonin agent. I think I also need to upregulate my 5HT2C receptors. I write additional thing on that two topic above, my nickname on that forum is enricks, btw.