New interesting PSSD theory (hyperammonemia)

[surviveplz]

Note: this is only a hypothesis. No medical advice. repost from PSSD forum

So now we have a guy cured from SIBO (lastround360), guys cured from FMT (blauwasser). Guys diagnosed with lyme disease, parasites, c.diff

I think a big part of PSSD symptoms are due to hyperammonemia, all those infections raise ammonia. I think hyperammonemia is the common denominator in all the different PSSD cases we see. User brooks already posted his hypothesis, he thinks the cause of hyperammonemia is genetic, I think it is acquired. It has nothing to do with the ARG-2 gene variant.

Acute ammonia induces NMDA receptors (anxiety), chronic low grade ammonia blocks NMDA receptors (absence of anxiety). Ammonia is a potent neurotoxin and it can lead to low grade encephalopathy of the brain. https://www.researchgate.net/publication/6139046_NMDA_receptors_in_hyperammonia_and_hepatic_encephalopathy

This low-level encephalopathy can not always be seen on MRI. SPECT/QEEG scans might be more useful (mine shows less activity in frontal lobe)

[quote]Hyperammonemia would be therefore responsible for the possible increase in “GABAergic tone” in HE. However, there are no reports studying whether hyperammonemia increases or not “GABAergic tone” in brain in vivo. The aim of this work was to assess whether “GABAergic tone” is increased in cerebellum and/or cortex of rats with chronic hyperammonemia.
Increased “GABAergic tone” means increased activation of GABA receptors and of associated processes. One process modulated by GABA receptors is the function of the glutamate-nitric oxide-guanosine 3′,5′-cyclic monophosphate (cGMP) pathway. Activation of N-methyl-d-aspartate (NMDA) receptors leads to activation of nitric oxide (NO) synthase and increased formation of NO, which activates guanylate cyclase, increasing cGMP, which is released to the extracellular fluid, allowing the assessing of the function of this glutamate-NO-cGMP pathway in brain in vivo by microdialysis.10
Activation of GABAA receptors reduces the function of this pathway in cerebellum11
and in cerebral cortex.12
Increased “GABAergic tone” would lead to reduced function of this pathway.
The function of this pathway and extracellular cGMP is reduced in cerebellum of hyperammonemic rats,13
which could be due to increased “GABAergic tone.” Blocking GABAA receptors must eliminate the effects of increased “GABAergic tone” resulting in increased function of the pathway and extracellular cGMP. To assess whether “GABAergic tone” is increased in hyperammonemic rats, we tested whether blocking GABAA receptors with bicuculline increases extracellular cGMP in cerebellum and/or cortex of hyperammonemic rats.[/quote] -> https://www.gastrojournal.org/article/S0016-5085(08)02315-9/fulltext

This study correlated with the QEEG images, less activity in frontal lobe. its the absence of anxiety

“Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors.”

“Hyperammonemia increased GABAergic tone in cerebellum but decreased it in the cerebral cortex of rats. Increased GABAergic tone in the cerebellum of rats with hyperammonemia could have been caused by increases in extracellular GABA; tetrahydrodeoxy-corticosterone (a neurosteroid that enhances GABAA receptor activation); or amounts of the α1, α6, and γ2 subunits of GABAA receptors. The decrease in GABAergic tone observed in the cortex could have resulted from the reduced amount of GABAA receptors δ and γ2 subunits or increased levels of pregnanolone (5-fold), which selectively reduces activation of GABAA receptors that contain α4 subunits (widely expressed in cortex but not in cerebellum). Treatment with bicuculline normalized GABAergic tone and restored the increase in cGMP that was induced by activation of N-methyl-d-aspartate receptors and learning ability in hyperammonemic rats.”

Be it gut dysbiosis, SIBO, c.diff, lyme - all those infections raise ammonia. Serum level does not necessarily correlate to brain levels. It’s difficult to measure. Maybe some of you already noticed that your body smells different (or even pee) .
I think this is due to ammonia buildup. Also the head pressure we have - its the encephalopathy. You can test this hypothesis by trying reishi (with high tripertene content) and beta glucans in form of oat bran and lions mane (together), this unloads the Purine nucleotide cycle and leads to increase of ammonia via reishi and beta glucan influence on IMP (Inosine monophosphate) - when I did this my head pressure increased big time and I could not move from bed for 4 days. (This is because it creates a flood of backlogged ammonia), we have N=2 experiences with this, user PsychoGenesis replicated this experience. Normal people don’t get knocked out with reishi and beta glucans.

Occurrence

This cycle occurs in skeletal muscle myocyte’s cytosolic compartment. This reaction helps to dispose AMP produced after following reaction.

ATP → ADP + Pi (utilisation of ATP for Muscle contraction)

2 ADP → ATP + AMP (catalysed by adenylyl kinase/myokinase)

Purine nucleotide cycle occurs during strenuous exercise, fasting or starvation when ATP reservoirs run low.
Consequences

1. Synthesis of fumarate

Fumarate is an intermediate of TCA cycle and enters the mitochondria by converting into malate and utilising the malate shuttle where it is converted into Oxaloacetic acid (OAA). OAA either enters into TCA cycle or converts into aspartate in the mitochondria. Aspartate can re-enter purine nucleotide cycle.

Oxaloacetic acid + Glutamate ↔ α-Ketoglutarate + Aspartate ( Catalysed by Aspartate Aminotransferase)

2. Synthesis of ammonia (Ammonia genesis)

The glutamate produced by OAA as above gains an NH3 to become a Glutamine and enters the circulation to reach kidneys. In kidneys, glutamine is deaminated twice to form glutamate and then α Ketoglutarate. These NH3 molecules neutralise the organic acids (lactic acid and ketone bodies) produced in the muscles.

purine nucleotide cycle is in top left

The thing I don’t quite understand yet is why supplements like LOLA (L-ornithine L-aspartate) or sodium benozate don’t lead to vast improvement of symptoms. I think this is because our body produces more ammonia than can be excreted by the liver/kidneys. Maybe glycerol phenylbutyrate could provide more relief, but it is very expensive.

Some cases reported windows after high dose of probiotics, which might have been due to their effects of total ammonia production from the microbiome - if there is dysbiosis (even “good” species overgrowth") - can lead to hyperammonemia - then by introducing a big dose of the right probiotics one can increase the ammonia scavenging bacteria. Antibiotics can also reduce the amount of ammonia producing bacteria.

A cure in this case might be FMT. For other infections, it might look different.

Heres a list of things that might be helpful…

• Full microbiome report (c.diff, giardia, ammonia producing bacteria)
• coxsackie, EBV
• parasite stool test (e.histolytica, etc)
• lyme disease and co-infections (rickettsia, mycoplasma, chlamydia), CD57-test
• BUN
• CBC
• Metabolic panel (will include ALAT, ASAT)
• don’t expect ammonia to be high (serum level does not correlate to brain levels necessarily)
• ANA
• B12
• Iron studies
• serum total IgG, IgE, IgA
• HTMA test
• Great plains tests (Mycotoxins, Organic Acids, Microbiology)
• SIBO test

What is the mechanism behind this? How do we suddenly get those infections? The answer is I think one of the predisposing factors of PSSD is existing dysbiosis/infections in our body. The SSRI / withdrawal was the trigger. It explains one pill cases, it explains the PSSD cases which got it from wellbutrin or other non serotonergic substances. It has more to do with the immune system, although serotonin also influences the immune system. It explains why we get it mainly in withdrawal - in withdrawal cortisol, which is immunosurpressive, rises.

Where do the sexual symptoms come from?

Hyperammonemia causes issues with cAMP and cGMP, cialis and viagra corrects some of it, however you need to adress the hyperammonemia.

Hyperammonemia impairs the function of the glutamate–NO–cGMP pathway in the cerebellum in vivo by reducing NO-induced activation of soluble guanylate cyclase. The effects of NMDA or SNAP on extracellular cGMP in the cerebellum of control, hyperammonemic rats without liver failure (2a and 2b) and with chronic liver failure (2c) were analyzed by in vivo microdialysis in freely moving rats.

Erectile dysfunction is a common, multifactorial disorder that is associated with aging and a range of organic and psychogenic conditions, including hypertension, hypercholesterolemia, diabetes mellitus, cardiovascular disease, and depression. Penile erection is a complex process involving psychogenic and hormonal input, and a neurovascular nonadrenergic, noncholinergic mechanism. Nitric oxide (NO) is believed to be the main vasoactive nonadrenergic, noncholinergic neurotransmitter and chemical mediator of penile erection. Released by nerve and endothelial cells in the corpora cavernosa of the penis, NO activates soluble guanylyl cyclase, which increases 3’,5’-cyclic guanosine monophosphate (cGMP) levels. Acting as a second messenger molecule, cGMP regulates the activity of calcium channels as well as intracellular contractile proteins that affect the relaxation of corpus cavernosum smooth muscle. Impaired NO bioactivity is a major pathogenic mechanism of erectile dysfunction.

https://www.researchgate.net/figure/Hyperammonemia-impairs-the-function-of-the-glutamate-NO-cGMP-pathway-in-the-cerebellum-in_fig2_24398873

The role of nitric oxide in erectile dysfunction: implications for medical...

Predispositions
-Infections, heavy metals, parasites, mold
-Ammonia clearing genes
-probably metabolization of SSRI

sibo: https://www.reddit.com/r/PSSD/comments/q03uci/gut_microbiota_theory_how_i_finally_cured_my_pssd/
c.diff: https://www.reddit.com/r/PSSD/comments/qhi2og/c_difficile_diagnosis/
lyme: https://www.gofundme.com/f/help-albin-get-lyme-disease-treatment (this is this user: https://pssdforum.org/viewtopic.php?f=41&t=2999&p=29177)
gut dysbiosis: https://pssdforum.org/viewtopic.php?f=20&t=2324&hilit=blauwasser
parasite + SIBO: https://www.curezone.org/forums/am.asp?i=2359277
gut dysbiosis: https://pssdforum.org/viewtopic.php?f=10&t=924&p=8167&hilit=probiotics+enema#p8167
gut dysbiosis: https://pssdforum.org/viewtopic.php?f=20&t=4417&hilit=brooks&start=40 (see section with probiotics)
lyme: https://www.reddit.com/r/anhedonia/comments/pzacji/for_those_that_struggle_with_anhedonia_after_ssri/hfer14l/?context=8&depth=9 (user also active in PSSD subreddit)
parasites: https://www.reddit.com/r/PSSD/comments/qaybor/got_my_results_gut_connection/

This is the best theory for PSSD I could come up in 3 years now, it explains the cognitive issues, the anhedonia, fatigue, absence of anxiety, head pressure, the sexual symptoms and everything.

Note: This is no scientific paper, I tried to explain it as best as I could, I am not able to write a scientific paper in this state, see the image of my brain above. If anyone gets cured… and has more evidence for this theory, please reply to this thread so we can actually write a scientific paper. Would be great, if someone with a working prefrontal cortex could assist in this.

Edit1:

For gut dysbiosis, it seems equally important to look at “beneficial flora” as “dysbiotic flora”, because beneficial flora, in excess can cause issues with ammonia aswell.

These are my results, bacteroides, e.coli, clostridium are ammonia producing ones. https://www.fixyourgut.com/upper-gut-dysbiosis-anxiety-brain-fog-fatigue-and-ammonia/

[Cbrandel]

If this were true, how can it be localized in the brain?

If the gut produces extra ammonia, but serum levels are normal. How do the ammonia end up in the brain? Surely it would have to be transported with the blood?

Unless the infection is located inside the brain.

Or am I missing something?

[surviveplz]

I think it depends on infection… for example lyme can directly go in brain, other infections raise systemic ammonia levels , etc. I just meant that you can have a low serum ammonia level but it can be still high in the brain, like its the case in lyme disease.

@vincentv made some progress here, however he stopped posting. I saw he posted about infections, ammonia, he even did this cd57 test … but he was not quite sure what he suffered from or what was his main problem IIRC

[slick1]

so what’s the treatment for ammonia excess ?It should give the relieve of the symptoms at least.
Ok i found it.