Capsaicin-like

[Progecitor]

I have just potentially discovered the origin of my POIS and it is called anandamide (AEA).

I may have been here for a short time, but I must thank you for making such a great site and for all the comments that I could search in. These gave me ideas I wouldn’t have had otherwise.

Although at first I wanted to find a link between the self-theorized capsaicin-like compound and opioids it turned out that it might just be a well known endocannabinoid. Interestingly this compund might be actually a link between the two analgesic systems. I have written most of the text by the time I realized this and I was lazy to rewrite the whole so I am sorry for any incongruity.

Previously I might have not emphasized enough that the compound I place behind the initiation of the whole POIS cascade (at least in my case) has the exact same properties as capsaicin which causes a burning pain. Although it can’t be that of course, but it has to be some kind of endogenous capsaicin-like compound. Following this aspect and also considering the participation of opioid receptor modulation in disease etiology some interesting links can be found.

As heat effects and capsaicin activates transient receptor potential vanilloid 1 or TRPV1, this also must be so in this case. Capsaicin is also known to contribute to beta-endorphin release as it serves as an analgesic (pain lowering) and antinociceptive (noxious stimuli (pain, thermal etc.) lowering effect) reaction.
Searching about this I found a study which lists quite a few connection between opioids and TRPV1 which is rather intriguing.
https://www.sciencedirect.com/topics/neuroscience/capsazepine
(scroll down to Opioids and TRPV1 Receptors)
What these researchers found:
- Both TRPV1 and opioids are involved in pain modulation.
- TRPV1 and opioids may interact in pain perception and reward.
- TRPV1 knockout mice do not develop thermal and tactile hypersensitivity following sustained morphine administration.
- Capsazepine as a TRPV1 antagonist is able to attenuate both morphine tolerance and dependence signs.
- Capsaicin is able to change the affinity of endogenous opioids such as endomorphin-1 to their receptors.
- Opioids are able to decrease or increase TRPV1 gene expression in the brain and spinal cord.
- Opioids through activation of PKA, PKC, and signaling molecules are able to modulate TRPV1 function.
- TRPV1 receptor antagonist decreased morphine-induced phosphorylation of p38 and NF-kB and increased AC1 in the dorsal striatum of rats.
- The interaction between opioids and TRPV1 opens a new window to clarify some unexplained questions regarding the effects of opioids.

I still don’t understand how this all comes together, but these facts must be still at the core of the issue.

This capsaicin-like pain is one of the most permanent symptom and although most evident in acute phase, but an itchiness still lingers in chronic phase and this is why I think that POIS never actually stops, it only becomes weaker. Actually it is quite apparent to me that the strength of the symptoms is quite linear with the actual concentration. So by definition it is much closer to a self-poisoning (hence the term POIS is quite appropriate) than an escalating allergy. The only thing that deceives us that the greatest release happens suddenly at the moment of O. The burning sensation is most prevalent in the feces, but is often felt during urination too and only sometimes in the semen during ejaculation.

As the itching of the anus is most often linked to parasitic infection this was one of my first suspicion too. To cut it short I had parasitic laboratory tests (both protozoan and helminths) from stool samples five times, but all were negative. I even took antiparasitic medication (Metronidazole) a few times and it did nothing to POIS.
The bacteriological findings were more interesting, but still inconclusive. I had bacterial identification tests from stool for seven times. The tests were usually the day after ejaculation or only a few days after, but still in acute state. So in order:
1st: Aside from normal E. coli count Klebsiella sp. was present in great number.
2nd: Normal E.coli were not present altogether.
3rd: Normal flora is present in very small number. Aside from normal E.coli count Klebsiella sp. was in great number. (I think after this I had Cyprofloxacin treatment which is an antibiotic)
4th: Salmonella, Shigella, E.coli O124, Yersinia enterocolitica and Campylobacter were not present. (I think this means a normal finding.),
5th: same as 4th,
6th: same as 4th plus Salmonella Typhi negative, Salmonella Paratyphi negative,
7th: same as 4th (this was a few years later and recently and the only one in the chronic phase).
One would think that Cyprofloxacin solved the problem, but it may not be so. I think I stopped eating whole grain bread somewhere along the way, which intensified POIS to a great degree, so it might be that too. I wanted to use the 7th as reference and do some acute tests with enhancing foods, but the pandemic just came in and I didn’t dare to go to the laboratory. The 2nd test also worth mention. I clearly remember that I did an O the day before, but everything was as usual, so I was not feeling especially unwell. The test also doesn’t necessarily mean that my whole gut flora died off, it might have only been at the rectal region. It seems strange that the supposedly pathogenic Klebsiella sp. couldn’t cope with the environment and also died off. I also don’t think that a normal acute state can easily kill off bacteria as even at the time of the first test I had already had POIS for more than 15 years and I only had more severe diarrhea cases in the first 10 years. Still the conclusion I can draw as of yet that it is indeed a mildly toxic chemical compound that is released and Klebsiella either metabolizes the compound better or is more resistant and dies off harder. Anyhow capsaicin is also known to be able to kill bacteria.

Urine tests are consistently negative in major parameters and no bacteria can be detected even with the burning sensation. The only parameter that is always high is specific gravity (1.030<), but my doctor says it is actually a good thing, although I am not so sure in that regard.

By the way medical examinations found prostate to be completely normal at Urology, anus with mild irritation at Proctology and nothing was abnormal with laparoscopy (2 times) and contrast X-ray intestinal examination at Gastroenterology. Furthermore gastric laparoscopy and abdominal sonography (3 times) found nothing.

To tell you the truth I had done some quite bizarre tests as I felt myself in dire straits, especially as I thought at the time that I was the only one on the whole world suffering from this disease. So one of these was when I put one finger into the anus at the site of the prostate during masturbation. As it turns out right at the moment of ejaculation the whole rectum seems to be engulfed by this capsaicin-like pain. I haven’t tested this extensively, but it seems that sometimes this pain is milder than usual and POIS symptoms are also weaker at the time. I also noticed that after around 7 days at the acute-chronic phase turnover this pain almost disappears and only an itching feeling remains unless I eat some POIS enhancer food which can raise pain and contribute to symptom manifestation (like red eyes). Of course I had a strong suspicion about this as often the pain was so excruciating after O that I was hardly able to wash my ass or was almost unable to defecate just as if I had eaten a whole bucket of extra hot chili pepper which I didn’t. It is also strange that the pain cannot be felt on the inside unless the lumen is touched, which might be the phenomenon of mechanical allodynia (an aspect of TRPV1).

Another bizarre test I did was to do a kind of enema. I only did this once in acute POIS, but it is apparent, that flushing out stool causes an instant clarity both in vision (blurriness) and thinking (mind fog). Other POIS symptoms also subsided, but these were the most apparent. Unfortunately it doesn’t stop POIS as it starts to build up right away and seems to be the usual by next day. This is no wonder as compound release is up-regulated in acute POIS and only comes down by chronic phase where its level becomes fairly stabilized. I also noticed many times when POIS was intense defecating could bring a sudden clarity both to vision and thinking. This must mean there is an equilibrium in the compound’s concentration between bowel faecal phase and the blood stream. When intestinal concentration drops it lowers in blood too and so symptoms regress, thus it is really a linear disease.
This also means that this compound is probably a small one as it seems to be able to easily pass the blood-brain barrier (BBB). This compound must have a very low toxicity as it doesn’t seem to do any permanent damage, but its irritating effect is high and can probably disregulate other biological mechanisms.

Now here comes the big question of whether this pain is real or just a perceptual feeling. Of course doctors would say that it is a perceptual phenomenon as hyperalgesia is just the term that seems to define this well. There is actually a kind of opioid induced hyperalgesia (OIH) that occurs after chronic high dose opiate (like morphine) usage. In this case the normally analgesic effects of opiates turns to hypersensitivity and pain effects become enhanced. This is possibly the reason why consuming poppy seed (opioid alkaloids) enhances the discussed pain effect. As from my point of view POIS is perpetually present even in chronic state so endogenous opioid release must be elevated at the time of O when an even greater compound release which could lead to aforementioned opioid induced hyperalgesia.
Some further information that seems interesting in this regard:
OIH may be more formally defined as increased nociceptive sensitization caused by exposure to opioids.
Spinal dynorphins also may play a role in OIH by increasing the presence of excitatory neuropeptides which can enhance nociceptive input. Also sometimes NMDA antagonists are able to alleviate OIH. Naloxone might intuitively make sense to use for OIH and has been shown in animal studies to help the antinociceptive effects of opioids but do not seem to modulate or reverse the effects of OIH.
Besides pain OIH can cause low mood, short-term memory problems and allodynia.
Animals given repeated systemic or intrathecal boluses of opioids developed progressive hyperalgesia to thermal or mechanical stimuli over the course of several days. Where studied, the time course of resolution of OIH was similar to the time course of its development. Of particular interest is a study by Celerier et al. documenting that animals with normal noxious sensitivity after recovering from OIH expressed recurrent and robust hyperalgesia if challenged with a single bolus of either drug, an opioid agonist or antagonist. These findings have two important implications. First, animals apparently recovered from OIH remained sensitized to the hyperalgesic effects of opioids. Second, this sensitization most likely was opposed by an endogenous opioidergic system, because the injection of an opioid antagonist unmasked hyperalgesia. This implies that OIH resolved because of upregulated inhibitory pathways opposing activity of sensitized excitatory pathways rather than the desensitization of excitatory pathways. According to this concept, resolution of OIH occurred at a new equilibrium of high neuronal activity between excitatory and inhibitory pathways (fig. 1). It is conceivable that an equilibrium achieved at a high level of neuronal activity is prone to derangements, which in a clinical context may translate into increased vulnerability to pain.
Opiate receptor-active peptide fragments (exorphins) were also identified in casein and gluten hydrolysates.

https://pubs.asahq.org/anesthesiology/article/104/3/570/8782/Opioid-induced-HyperalgesiaA-Qualitative
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550256/
https://academic.oup.com/painmedicine/article/16/suppl_1/S32/2472483
https://www.uspharmacist.com/article/opioid-induced-hyperalgesia-an-emerging-treatment-challenge
https://casereports.bmj.com/content/2014/bcr-2014-204551
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30430-1/fulltext?rss=yes
https://link.springer.com/article/10.1007/s12035-019-01650-5

So there is a good possibility for OIH, but even capsaicin can lead to “normal” hyperalgesia so it not necessarily the case. I also think that hyperalgesia plays the smaller part (as the cause of IBS symptoms) and a direct chemically induced pain has to be the primary cause.
There are several reasons to it:
- Sudden appearance of pain: Even if there is a change in microbial fermentation it simply can’t be instantenous.
- Bacterial flora can die off or become suppressed. I don’t think the mere feeling of pain would be able to do this unless there was a highly concentrated chemical. It is also unlikely that bacteria would kill itself.
- Charcoal being effective, although it also up-regulates pain effect after a short time.
- Excretion (both stool and urine) reduces symptoms. Stool quality is apparently abnormal (dark (not blood) and sticky) and urine is often frothy.

The most intriguing fact is that capsaicin itself produces a reversible antinociceptive and antiinflammatory action after an initial undesirable algesic (pain causing) effect. This means that it induces nociception at first (TRPV1 activation), but also causes desensitization which leads to antinociception. Substance P release is up-regulated (mast cell activator), but it becomes depleted as desensitization occurs.

https://www.sciencedirect.com/science/article/abs/pii/002432059290045Q
https://www.sciencedirect.com/science/article/abs/pii/S002839080300100X

Capsaicin promotes blood flow to tissues by lowering blood pressure and stimulating the release of nitric oxide and other vasodilators. Vasodilators are compounds that help expand your blood vessels, allowing blood to flow through more easily.
Heat, humidity, bathing in warm water, or sweating may increase the burning sensation.
Although capsaicin can cause neurogenic inflammation per se under certain physiologic conditions, it also has analgesic and anti-inflammatory activities.

https://en.wikipedia.org/wiki/Neurogenic_inflammation
https://www.mdpi.com/2072-6643/8/5/174/htm

Some google facts about the effects of capsaicin:
After a few weeks of use, the burning sensation is often less of an issue and deeper pain-relieving benefits grow. Capsaicin appears to reduce a chemical - substance P - that sends pain signals to the brain. It often takes a week or two, therefore, to get maximal benefit.
Capsaicin will also cause a release of SP and calcitonin gene-related peptide (CGRP) from peripheral and central nerve terminals, contributing to the local flare (neurogenic inflammation) [Winter et al.].
The most common reason people sweat when they eat involves spicy foods like peppers. Peppers have a chemical called capsaicin that triggers the nerves that make your body feel warmer, so you sweat to cool it back down.
Capsaicin is more soluble in oil or alcohol than in water, thus they can mobilize it.
Vinegar: Acetic acid neutralizes the alkalinity of capsaicin. Pour it over hands or contaminated skin. It's also safe to soak skin in a mixture of vinegar and water for 15 minutes. Additionally, you can rinse your mouth with vinegar to relieve hot pepper burn.
Capsaicin is not soluble in water, which is why running your hands under cold water probably wouldn't do much for the burn. But the casein protein in milk (or cream, as per grandfather) can grab onto capsaicin and help neutralize it.
Activation of TPRV1 by its specific agonist capsaicin promotes endothelium-dependent vasodilation and subsequently contributes to lower blood pressure.

To be precise as I mentioned at the beginning the initiator compound is not capsaicin, but something similar, so it doesn’t necesserily mean that everything is the same. Although it may be possible that some health benefits of capsaicin might be present even in our ill state like a reduced chance of being obese or getting diabetes and it may even has an anti-cancer property not that it is a happy (also unproven) consequence.

Actually all seems to come down to the terms of nociception and anti-nociception. Aside from opioid agonists and antagonist the other drugs that seems to modulate (either positively or negatively) POIS state are nociceptive and antinociceptive compounds.
Compounds that have antinociceptive property: capsaicin, testosterone, quercetin, rutin (partly opioid mediated), kaempferol, ?-endorphin, morphine, melatonin (induces ?-endorphin release), taurine (naloxone blocks this effect!), turmeric (curcumin), Piper nigrum (black pepper), Diclofenac, ketamine, magnesium, zinc, apple cider vinegar, niacin and thiamine (their deficiencies can enhance nociception), B-vitamines (especially B1 (thiamine) and B12 (cobalamin)), Citrus limonum (lemon), sulforaphane, some herbs with anti-nociceptive potential (by random search): lemongrass (citronellal) – also a weak capsaicin antagonist, dandelion, Cistus albidus, Lonicera japonica, Polygonum hydropiper leaves, Alkanna sp., Acronychia pedunculata leaves, etc.
Certainly this list seems controversial, but there might be a competitive behavior on TRPV1 activation and desensitization also has to be considered.

https://europepmc.org/article/med/8136733
https://journals.sagepub.com/doi/abs/10.1177/0022034509356169
https://jpet.aspetjournals.org/content/282/3/1319.short

The nociceptive and antinociceptive dual effect of ginger seems to be in line with capsaicin, but then why does ginger ameliorate pain while external capsaicin exacerbates it.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14766
http://naturalingredient.org/wp/wp-content/uploads/51-62.pdf

Nociceptive compounds: nitric oxide (NO), glutamate, aspartate, lactic acid, carrageenan, prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), bradykinin, excitatory amino acids (glutamate, aspartate, NMDA etc.)
https://journals.sagepub.com/doi/abs/10.1046/j.1468-2982.1994.1406437.x
 
The effect of serotonin on nociception is especially complicated. Nevertheless 5-HT3 seems to be most implicated receptor subtype and their antagonists (like ondansetron) should also be considered as POIS treatment candidates.
https://psycnet.apa.org/record/1991-23522-001
https://www.jpain.org/article/S1526-5900(11)00224-0/abstract
https://www.jneurosci.org/content/22/3/1010.full

Coffee (chlorogenic acids and related quinides are capable of inhibiting the morphine induced anti-nociceptive behavior)
https://www.researchgate.net/profile/Roseane_Santos3/publication/265124232_Santos_RM_Hunter_T_and_Lima_DR_Coffee_Depression_Alcoholism_and_Drug_Abuse_-_Mini-_review_Austin_J_Pharmacol_Ther_21_6_Jan_2014/links/551d5dcc0cf29a69c99b2df6/Santos-RM-Hunter-T-and-Lima-DR-Coffee-Depression-Alcoholism-and-Drug-Abuse-Mini-review-Austin-J-Pharmacol-Ther-21-6-Jan-2014.pdf

Capsaicin also activates substance P (SP) release, which is know to be a release initiator of many other inflammatory compounds like cytokines. Substance P can also control mast cell activation. Some antihistamines (like azelastine or cetirizine) may inhibit Substance P.
https://www.sciencedirect.com/science/article/abs/pii/S0006295200002604
https://pubs.asahq.org/anesthesiology/article/116/4/882/13128/Substance-P-Signaling-Controls-Mast-Cell
https://www.karger.com/article/pdf/234229
https://www.sciencedirect.com/science/article/abs/pii/S001429990101617X
https://journals.sagepub.com/doi/abs/10.1177/000348940411301201

Endovanilloids (EV):
Some other endogenous capsaicin-like compounds are N-arachidonoyl-dopamine (NADA), the endocannabinoid N-arachidonoylethanolamine (AEA) also called Anandamide, 12-Hydroperoxyeicosatetraenoic acid (12-HPETE) and 15-HPETE and leukotriene B4 (LTB4).
At first I thought that it must be NADA as its characteristics and effects are just what I seek, but then I realized that it only occurs in the brain and not in the intestines or prostate/testicles at least under normal circumstances. However it turns out that anandamide can actually be found in the prostate. Although anandamide has a weaker capsaicin like effect than either capsaicin or NADA, still if it is released in a very large amount it may just be the one responsible for all my ails.
Formerly I also thought about a possibility of AA-5-HT involvement. The interesting thing while they both act on endocannabinoid CB1 receptors they both also act on TRPV1 although NADA is an agonist, but AA-5-HT is an antagonist of TRPV1. Additionally 5 - N-Acyldopamine and N-Acylserotonin may play a role too.

https://en.wikipedia.org/wiki/N-Arachidonoyl_dopamine
https://en.wikipedia.org/wiki/Anandamide
https://en.wikipedia.org/wiki/12-Hydroxyeicosatetraenoic_acid
https://www.liebertpub.com/doi/full/10.1089/can.2017.0015
Check Table 2 for N-Arachidonoyl Dopamine Effects
https://www.sciencedirect.com/science/article/abs/pii/S0014299909009601
https://www.sciencedirect.com/science/article/pii/S0021925820387937
https://journals.physiology.org/doi/full/10.1152/jn.00395.2005
https://www.pnas.org/content/99/12/8400.full
https://www.pnas.org/content/97/11/6155.full
https://www.sciencedirect.com/science/article/pii/B9780124201262000055
https://royalsocietypublishing.org/doi/full/10.1098/rstb.2011.0392
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958632/
https://www.frontiersin.org/articles/10.3389/fnmol.2017.00152/full

Anandamide (AEA)

Whereas NADA is similar in potency to capsaicin in a variety of assays of VR1 activity, anandamide and 12-HPETE are at least 20-fold less potent than capsaicin.
All of the putative endovanilloids identified to date are products of arachidonic acid, an unsaturated long chain fatty acid with a primary role in inflammation and pain.
https://www.sciencedirect.com/science/article/pii/S0021925819645011

Ethanolamine can greatly increase anandamide biosynthesis in rat testes.
https://www.sciencedirect.com/science/article/abs/pii/S0009308497001096

Genes encoding for FAAH1 and FAAH2 are highly expressed in the human seminal vesicles (SV) and Vas deferens (VD).
https://www.auajournals.org/doi/10.1016/j.juro.2018.02.1409

FAAH were detected in the human prostate.
https://www.auajournals.org/doi/10.1016/j.juro.2014.02.530

Studies have broadly demonstrated the presence of cannabinoid receptors on sperm.
Cannabis reduces sperm count.
Cannabis causes morphological changes in sperm, but genetic material is preserved.
Cannabis can reduce sperm motility. (I think that it was indicated in the South-Korean case study.)
Effects of THC were more pronounced in washed sperm than in neat semen, suggesting that seminal plasma contains some protective factors.
The CB1 receptor antagonist rimonabant induced a small but significant increase in the number of viable spermatozoa.
Research suggests that the cannabinoid signaling pathway may be involved in inhibiting sperm capacitation and activation. Using high performance liquid chromatography Schuel et al observed that high levels of AEA are present in seminal plasma and in progressively decreasing amounts in oviductal and follicular fluid, indicating that sperm are exposed to progressively decreasing AEA levels along the entire fertilization path. The authors speculated that high AEA levels maintain sperm in a quiescent state and the decrease in AEA levels which occurs in the fertilization environment enables sperm to become activated. These data suggest that increases in cannabinoid levels may interfere with sperm activation and may be especially pertinent in the female reproductive tract, which the sperm depend on for tightly regulated AEA levels to maintain proper function.
This is actually the perfect evidence that an anandamide (AEA) overproduction is the cause of POIS (maybe not for all). As to why AEA production is so high I don’t really know, but it might have to do something with cannabinoid receptor sensitization. A doctor should really be asked about these facts, I can only do self-diagnostics as I don’t have one.
FSH may not be affected by cannabis except perhaps in the limited case of heavy chronic use.
In human and animal models LH is consistently lowered by cannabis.
The reported effect of cannabis on serum testosterone levels is widely variable across current studies. In an early work in 20 chronic marijuana users Kolodny et al found a significant reduction in testosterone levels between chronic and never marijuana users (p <0.001).12 The average plasma testosterone level in the control group was 742 ± 29 ng/ml, while levels were 503 ± 40 and 309 ± 34 ng/ml in the 5 to 9 and the 10 or more marijuana cigarettes a week groups, respectively (p <0.005).
https://www.auajournals.org/doi/10.1097/JU.0000000000000248

I wanted to suggest that some cannabinoid antagonists like rimonabant should be tried (applying it to the prostate as the problem is probably not systemic, but who knows), but it turns out that it has been banned. Interestingly and unexpectedly it also caused very similar problems as ours, namely flu-like symptoms which only adds to the mystery.
https://en.wikipedia.org/wiki/Rimonabant

A diet deficient of essential fatty acids induced a reduction of anandamide in several organs.
https://www.sciencedirect.com/science/article/abs/pii/S0952327819301322

Increasing the relative proportion of n–3 LC?PUFAs (ALA, EPA, DHA) in the diet can lead to a decrease in the formation of the ‘prototypic’ endocannabinoids anandamide (AEA) and 2?AG.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.12030

Anandamide seems to be involved in runner’s high. Well it seems that for me having a nocturnal emission is more than running a marathon.
https://en.wikipedia.org/wiki/Neurobiological_effects_of_physical_exercise#Euphoria

As fatty acid amide hydrolase or FAAH breaks down anandamide, it is possible that this enzyme has some kind of problem, but I think the problem is rather on the production part. Unfortunately it seems there are only FAAH inhibitor medicines, but there are no word of FAAH agonists.
https://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase

It would be logical to think that there is a serious problem with anandamide transport, but it is not even known if anandamide has a transporter or if it only passively diffuses through cell membranes.
https://www.sciencedirect.com/science/article/abs/pii/S0024320505004832

Anandamide can modulate endogenous opioid levels through a not yet known endogenous opioid (maybe dynorphin A).
It might be that actually this opioid causes the OIH.
https://www.sciencedirect.com/science/article/abs/pii/S0091305797005832

Anandamide can interact with kappa opioid receptor system and its effect can be blocked by mu and kappa opioid antagonists.
https://www.sciencedirect.com/science/article/abs/pii/S0014299908008741

Anandamide can ameliorate opioid withdrawal symptoms. It might be because it actually increases the release or maybe it enhances the antinociceptive properties of other endogenous opioids. It might have relevance for those POISers for whom THC, CBD actually works.
https://www.sciencedirect.com/science/article/abs/pii/0028390895000322

The synergistic effect of cannabinoid and morphine can actually lead to dynorphin A release.
https://www.researchgate.net/profile/Ercan_Ozdemir2/publication/282041409_The_effects_of_endocannabinoid_receptor_agonist_anandamide_and_antagonist_rimonabant_on_opioid_analgesia_and_tolerance_in_rats/links/5606457408aea25fce345a79/The-effects-of-endocannabinoid-receptor-agonist-anandamide-and-antagonist-rimonabant-on-opioid-analgesia-and-tolerance-in-rats.pdf

Paracetamol (called acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form AM404. This is an inhibitor of anandamide reuptake and leads to elevated anandamide levels. I haven’t taken paracetamol as I have Gilbert disease and I was told not to. It seems a prudent advice as it could really enhance my problems.
https://en.wikipedia.org/wiki/Anandamide

AEA can cause antinociception (capsaicin-like), hypothermia, and hypomotility, furthermore tolerance and withdrawal.
https://www.nature.com/articles/npp201044

The suppression of n-6 PUFA-derived eicosanoid production by n-3 PUFA may be caused by their competition for a common enzyme in the eicosanoid biosynthetic pathway, ?6-desaturase. Also, EPA, through its mono- and trihydroxy-derivatives, decreases the production of proinflammatory cytokines (e.g.IL-1?, TNF-?). Consequently, EPA-derived eicosanoids are considered to be less inflammatory potent than those derived from AA, and this is one of the main reasons that fish oil (containing EPA but also DHA) has been characterised as having antiinflammatory properties.
Products of non-enzymatic oxidation of AA and other 20 carbon atom FA (isoprostanes) are used as surrogate markers of oxidative stress.
https://biomed.papers.upol.cz/pdfs/bio/2011/03/01.pdf

The uptake of AEA into cells is unique in that its uptake is coupled to its breakdown by the catabolic enzyme FAAH located at the endoplasmic reticulum (Figure ?(Figure2).2). Uptake rates in different cells are generally correlated with inherent FAAH concentration and the rate increases further with transfection of FAAH (Day et al., 2001; Deutsch et al., 2001). Conversely, uptake rates are generally negatively correlated with the degree of FAAH inhibition, although in some cells other catabolic enzymes and their inhibitors may play a role, such as COX-2 and NAAA (Fowler et al., 2004, 2013; Glaser et al., 2005; Hillard and Jarrahian, 2005). FAAH removes AEA from inside the cell, disrupting the equilibrium between inside and outside the cell, generating a concentration gradient that drives uptake.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062061/

More about AEA synthesis and breakdown:
https://www.nature.com/articles/4401284
https://www.sciencedirect.com/science/article/abs/pii/S0952327801903564

It can be concluded that sex hormones down?regulate FAAH activity by reducing gene expression at the level of protein synthesis. This is a demonstration of a direct interplay between endocannabinoid degradation and sex hormones in mammals. Also anandamide synthase activity was measured in mouse uterus, and was found to respond to sex hormones in the same way as FAAH. Although it is still under debate whether or not anandamide hydrolase and synthase activities belong to the same or different enzymes, these data demonstrate that the two activities are under the same hormonal control.
https://febs.onlinelibrary.wiley.com/doi/full/10.1046/j.1432-1033.2000.01316.x

AEA may not modulate ethanol consumption, but I still don’t like it.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1460-9568.2007.05665.x

The endocannabinoid system (ECS) is a well-recognized effector of human energy homeostasis, and its dysregulation has been implicated in metabolic diseases.
Skeletal muscle anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important determinants of daily energy expenditure (EE) in humans, explaining a large amount of the interindividual variance in EE, particularly sleeping energy expenditure (SLEEP).
https://academic.oup.com/jcem/article/103/10/3757/5063487?login=true

AEA can modulate acetylcholine release.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0704220

The case of the Scottish woman who has FAAH-OUT seems interesting as she also has high AEA levels. Interestingly she only has a few similar symptoms like forgetting things midway and having an adverse reaction to morphine, but not to paracetamol. She doesn’t seem to have any brain fog, muscle fatigue or flue like symptoms. This may not be in line with the above, but I still believe there is an explanation for this. AEA may be high in both cases, but as FAAH is probably present in me it also breaks down rapidly. I haven’t had time to read everything about this, but it may be that the breakdown products have an even greater significance. The localization is also specific to the rectal region and intestine and probably it is what drives disbaceriosis (disfermentation) and leads to butyrate equilibrium imbalance.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676009/

And probably many more connections can be found, but I wanted to share this as soon as possible so you can check out for yourselves. I also haven’t had time to read up on the other POIS types, but even if it is not AEA you may still find some connection.
The following was written beforehand, but still might hold some importance.

N-Arachidonoyl Taurine (NAT) also acts like an endogenous capsaicin analog and it may have relevance for those POISers for whom taurine works. For me it doesn’t seem to work so far, but I have only tested it a few times and with smaller amounts.
“Moreover, activation by the endogenous activator N-arachidonoyl taurine (NAT), induced similar effects as capsaicin. On the other hand, taurine, the decomposition product of NAT, strongly depressed the evoked glutamatergic synaptic transmission.”
https://www.frontiersin.org/articles/10.3389/fnins.2020.00091/full

Bradykinin acting through B2 receptor is also a potent activator of TRPV1.

As autoantibodies are a possibility in our disease it may be that such an antibody could have a capsaicin-like property, although I couldn’t find any studies that would back up such a claim.
Cytokine and chemokine release is usually a consequence of TRPV1 activation and not the other way around, but some chemokines seem to be able to activate the vanilloid receptor so they deserve consideration.
https://link.springer.com/chapter/10.1007%2F3-7643-7423-3_9

There is still a possibility for lactic acid involvement too. Taking Lactobacillus probiotics, lactulose (although lactose intolerance negative), having muscle-fever due to excessive physical exercise (especially sit-ups) all seem to enhance this kind of burning pain. Eating wholegrain bread also enhances this burning, but it can’t be gluten as normal bread doesn’t have this effect and it might be that SCFAs production is up-regulated. Many fruits with a high ester content also enhances it. Sweet paprika is the most perplexing as it doesn’t contain capsaicin, but still results in a severe capsaicin-like pain and POIS symptom aggravation. If it is a psychogenic pain as my psychiatrist always says then it has to be my intestinal neurons who believe it is capsaicin as my mind certainly doesn’t.

Another disease that somewhat resembles POIS:
https://en.wikipedia.org/wiki/Cannabinoid_hyperemesis_syndrome

I have accidentally run into chronic nonbacterial prostatitis (chronic pelvic pain syndrome) and then realized that it is also often mentioned on this site. My theory and experiences seem to be well in line with this syndrome. The study I found first is actually about capsaicin induced prostatitis and the changes it induces in prostatic cannabinoid receptors.
https://www.health.harvard.edu/newsletter_article/chronic-nonbacterial-prostatitis-chronic-pelvic-pain-syndrome
https://www.auajournals.org/doi/full/10.1016/j.juro.2016.02.1648

As I final note I have to wonder if the up-regulation of a similar capsaicin-like compound plays a role in other similar diseases like ME/CFS or postcovid. The same compound’s release at an other bodypart might also result in a different manifestation. It might still be the reason why similar medicines work.

N-Acetylserotonin – NAS (a member of N-Acylserotonines) involvement is also indicated in orthostatic hypotension.
https://en.wikipedia.org/wiki/N-Acetylserotonin

Among others N-acetyl-tryptophan can be high in COVID-19 patients, but it is due to the disruption of tryptophan metabolism.
https://www.atsjournals.org/doi/full/10.1165/rcmb.2020-0206LE

Some theoretically (not proven) recommended supplementation during covid-19 based on (metabol/prote)omics: tryptophan, arginine, glutamin.
https://www.in.jpnim.com/index.php/jpnim/article/view/e100145/746
(you can safely bypass the warning)

It may not have any relevance, but here is a study that details the connection between prostate cancer and COVID-19.
https://www.nature.com/articles/s42003-020-1088-9?elqTrackId=eecce2f1a1ee4a3c9abf199c258e7795

Arachidonic acid (a metabolite of AEA) seems to be protective in COVID-19 and might be the link why testosterone works for us through ACE2 regulation.
https://www.sciencedirect.com/science/article/abs/pii/S0188440920312637?via%3Dihub

There are many more metabolomic changes in COVID-19, although it doesn’t necessarily reflect the postcovid state. Still some compound changes are similar to CFS metabolic changes like a decrease in spingolipids.
https://www.cell.com/cell/fulltext/S0092-8674(20)30627-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420306279%3Fshowall%3Dtrue

Metabolomics in CFS:
https://link.springer.com/content/pdf/10.1186/s12967-020-02356-2.pdf
https://www.mdpi.com/2218-1989/10/1/34/htm
https://www.nature.com/articles/srep34990
https://www.nature.com/articles/s41598-018-28477-9
https://www.pnas.org/content/113/37/E5472/tab-figures-data
Check out table 5. It is rather apparent that CFS values are in stark contrast with metabolic syndrome (related to diabetes).

I think a similar metabolomic and proteomic study in POIS could at least identify this capsaicin-like compound even if it didn’t solve its origin.
I think researchers should care more about our disease and not because we really matter, but rather because it would greatly help uncovering the connections between sexual activity and the human metabolism.

[Iwillbeatthis]

I can't smoke cannabis for five years now it causes bad bladder pain (interstitial cystitis?) CBD is the same for me as well, I also don't get a runners high ever can you explain what is going on maybe?

[b_jim]

Welcome. Thanks for such a brilliant post
I can only say that taurine still works for me... and I don't know why. I will try to understand your theory.

[Muon]

Hi Progecitor,

You may post some relevant papers in the comments of the thread below:

https://poiscenter.com/forums/index.php?topic=3127.0

I can take a look at a few and put them on page 1.

[Prospero]

There are many thought-provoking elements here. Thank you for taking the time to write your reflections at length. Some remarks though.

As for me, I don't have any pain in the rectum area (apart from haemorrhoids sometimes). Codein (soft morphine) and Tramadol, which act through mu-opioid receptors, have a positive effect, as well as Paracetamol. So I would not be concerned by your theory if it were true.

I also have Gilbert's syndrome and never had any problem with Paracetamol, so I wonder if you could try it at low dose (300 to 500 mg, timed after orgasm, are sufficient for me), in order to test your theory.
Same with codein, maybe. In a previous thread you mentioned that you had good results with a mu-opioid antagonist, Low-dose Naltrexone, but I've read that LDN could also stimulate the endogenous production of endorphins, so I'm not sure that you can draw definitive conclusions on your reaction to opioids without trying them.

Most importantly, I don't understand the link between arousal or orgasm and the production of anandamide. Would it be through the Arachidonic Acid pathway highlighted by nanna1 in his first POIS theory ?

[Journey]

So what then could be the root cause that those chemicals which are in excess which then cause POIS and the background symptoms have been present in the first place and how could we stabilize this underlying imbalance that causes the POIS and the background symptoms?

I too often feel weird kinds of warmth and itchiness and other sensations throughout my body and some times I have had warm burning stools and I often feel like something is inhibiting my body as in some microbe types or something like that.

Also in relation to this theory:

What could have made my POIS disappear when I had a cold in 2020 February? I had two orgasms and one nocturnal emission and zero brain fog, vision changes, motor changes, mental processing speed slowdown and I felt as if the post-orgasmic blood flow and overall warmth sensation was different and I felt more pleasure in the middle deeper area of the genitals which I have never ever felt when I have had POIS so that could mean there is some link this is the only time I have EVER had no POIS symptoms other than abstinence, please tell me what do you think could be involved or causing this POIS free effect?

[Progecitor]

I can't smoke cannabis for five years now it causes bad bladder pain (interstitial cystitis?) CBD is the same for me as well, I also don't get a runners high ever can you explain what is going on maybe?

I have some urinary problems, but they are not so severe. When I get to try CBD oil I will inform you about my experiences.

Welcome. Thanks for such a brilliant post

Thank you! I appreciate that you see the theoretical value. Doctors always think that I want to complain, but I just want to solve my problem. It is not my fault that it is so complicated.

Hi Progecitor,

You may post some relevant papers in the comments of the thread below:

https://poiscenter.com/forums/index.php?topic=3127.0

I can take a look at a few and put them on page 1.

I don't really have any more interesting laboratory test results. I only had general tests and they were mostly good even in acute phase. I wanted to write about them anyway and about my more peculiar symptoms (like recurrent chest pain), but I haven't had time so far. I will put it under the medical test results thread in one block maybe in a few weeks.

There are many thought-provoking elements here. Thank you for taking the time to write your reflections at length. Some remarks though.

As for me, I don't have any pain in the rectum area (apart from haemorrhoids sometimes). Codein (soft morphine) and Tramadol, which act through mu-opioid receptors, have a positive effect, as well as Paracetamol. So I would not be concerned by your theory if it were true.

I also have Gilbert's syndrome and never had any problem with Paracetamol, so I wonder if you could try it at low dose (300 to 500 mg, timed after orgasm, are sufficient for me), in order to test your theory.
Same with codein, maybe. In a previous thread you mentioned that you had good results with a mu-opioid antagonist, Low-dose Naltrexone, but I've read that LDN could also stimulate the endogenous production of endorphins, so I'm not sure that you can draw definitive conclusions on your reaction to opioids without trying them.

Most importantly, I don't understand the link between arousal or orgasm and the production of anandamide. Would it be through the Arachidonic Acid pathway highlighted by nanna1 in his first POIS theory ?

I haven't had time to check the symptoms for other types of POISers, but you may have some kind of withdrawal type POIS. I think it may be possible that you have a really low level of some kind of similar endogenous opioid or cannabinoid and it unbalances homeostasis. As to how it would relate to sexual activity I am even more unsure. Maybe during orgasm you lose even that small amount you have and precipitate symptoms or it actually increases, but it gets lower again and causes withdrawal until a new balance is reached. The time of onset of symptoms could also indicate a slow or fast reaction, although I have elevated symptoms even before O. But a theory is only a theory until proved and has to be tested out even if it may sound sound at first even if it is mine. You may give a try to capsaicin too if you haven't already. If I remember well it might even have some weak agonistic effect on cannabinoid receptors too. It can possibly lower cancer chance if you have a low anandamide level by chance. You could also try eating my blacklist foods, although I haven't figured it out why they enhance my POIS.
Three days ago I didn't even know that paracetamol was indicated in my disease. I will definitely give it a try to see how symptoms are effected.
Unfortunately I couldn't try naltrexone as of yet. I only said that when I had serotonin deprivation
syndrome all my POIS symptoms disappeared and I had very similar side effects. Serotonin definitely has something to do with my disease. Taking a moderate dose of tryptophan helps me, but at a high dose I develop a transient orthostatic intolerance and some POIS symptoms can still be felt.
At one point I thought I might have a low level of N?arachidonoyl?serotonin (AA?5?HT), but just now I can't recall why. AA-5-HT has an agonistic effect on cannabinoid receptors, but antagonistic effect on TRPV1 receptors. I have also just realized that it inhibits FAAH that leads to an increased AEA level. This might just explain why I experience some kind of dual effect with serotonin, but its positive effects still outweigh its negative ones.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0707145
Now we at least know that AEA can be found in the seminal plasma in relatively high amounts even in healthy persons. Even if you don't have any problems with AEA it might still set of a cascade of events  at O as its activity is tightly linked to other endocannabinoids like NADA, AA?5?HT, 2-AG, PEA, etc. and a malfunction in those would be revealed.
For your last question I can't answer as of yet as I am only beginning to consider its implication for myself. I will try out as many of nanna1's recommendations as I can although it will take a lot of time.

So what then could be the root cause that those chemicals which are in excess which then cause POIS and the background symptoms have been present in the first place and how could we stabilize this underlying imbalance that causes the POIS and the background symptoms?

I too often feel weird kinds of warmth and itchiness and other sensations throughout my body and some times I have had warm burning stools and I often feel like something is inhibiting my body as in some microbe types or something like that.

Also in relation to this theory:

What could have made my POIS disappear when I had a cold in 2020 February? I had two orgasms and one nocturnal emission and zero brain fog, vision changes, motor changes, mental processing speed slowdown and I felt as if the post-orgasmic blood flow and overall warmth sensation was different and I felt more pleasure in the middle deeper area of the genitals which I have never ever felt when I have had POIS so that could mean there is some link this is the only time I have EVER had no POIS symptoms other than abstinence, please tell me what do you think could be involved or causing this POIS free effect?

I don't even know if I have primary or secondary POIS. I think I first masturbated at the age of 11 and I  am sure I had IBS symptoms when I was 13. It doesn't mean I didn't have other POIS symptoms from the first time, but I might thought at the time that it was a normal issue. I was in high school when I realized that it has to do with masturbation and kept it a secret even from my relatives as one normally doesn't speak of such things. I always wondered if it was genetic or if it was somehow my fault. Around the age of 13 I masturbated quite a lot as there were days (not every) when I did it 5-6 times a day. Also someone one the forum mentioned that he developed POIS (I am not sure which type) in a period, when he consumed a lot of cannabis and had a lot of sex too. It might have been the case with me too. Of course I didn't consume cannabis, but normal enhancing foods might had had a similar effect and I might had been susceptible to developing POIS for all I know. Nonetheless even before the age of 11 I was quite a euphoric kid (Isn't everyone?) and showed some slight autistic behavior too. I also had a left testicular hydrocele when I was a few years old and had a minor surgery. It might not has to do anything with POIS, but it might have been present in its chronic phase even then without me realizing it.

About the other issue I generally I also don't really feel any pain either. I think the best way to put it is like imagine you eat a small amount of hot paprika or chilli pepper every time you eat and you would feel about the same during excretion. I don't even have severe pain anymore. It usually happened when I ate some enhancing foods (even paprika without capsaicin) and had very acute POIS at the same time. Pain is usually mild or only a warm feeling is felt or an ichyness occurs. Anandamide is 20-fold less potent than capsaicin, so even a mild burning feeling would mean that it has to be present in really great amounts.
I think you might have a similar POIS as mine.

I might have had reduced POIS during some illness, but I only heard about such a possibility a short while ago so I am not sure. One usually doesn't masturbate during an illness anyway so POIS would lower likewise. I think I had some extended illnesses (usually tonsillitis) when masturbating brought a relapse in subsiding disease too.
You might still be right, but I can only give you theories and nothing definite.
You could consider capsaicin and anandamide as they both seem to have proinflammatory and antiinflammatory effects to. This could have implications, but I am really not well versed in this regard.
You could also consider COVID-19 where they found that arachidonic acid may have a protective role against the virus. I was also wondering about sphingolipids, because it seems that AEA increases its production through ceramid production, but their level seems to be low in both CFS and COVID-19. Actually I haven't had the time to read the full article so you should check for yourself if you are interested. The same goes for cholesterol as anandamide can lower its level and maybe it can lower coagulation too. Anandamide could be the miracle cure for COVID-19 and the cause of postcovid at the same time for all I know and I really don't know.
Some POISers had mild symptoms during COVID-19, but I just don't know which type of POIS they have and it might be that some POIS types are very susceptible to it, so be really careful nonetheless.
And even if you are really resistant to it you might just be really unlucky and still die.
So even if you check everything out you won't know for sure, but theories can always be formulated.

In the meanwhile I have just found this:
Anandamide can be eliminated with polymixin B.
https://link.springer.com/article/10.1007/s00540-005-0366-5
It is not a cure of course, but maybe a possible treatment.

By the way I dropped out of university (due to my illness) and work as a kind of part time janitor and you shouldn't expect a very professional advice from a janitor I think.

I am also sorry about the apostrophe. I just don't know what to do besides retyping all of them. I usually write my text in office and then copy-paste, but it seems that it results in an error.

[Journey]

I can't smoke cannabis for five years now it causes bad bladder pain (interstitial cystitis?) CBD is the same for me as well, I also don't get a runners high ever can you explain what is going on maybe?

I have some urinary problems, but they are not so severe. When I get to try CBD oil I will inform you about my experiences.

Welcome. Thanks for such a brilliant post

Thank you! I appreciate that you see the theoretical value. Doctors always think that I want to complain, but I just want to solve my problem. It is not my fault that it is so complicated.

Hi Progecitor,

You may post some relevant papers in the comments of the thread below:

https://poiscenter.com/forums/index.php?topic=3127.0

I can take a look at a few and put them on page 1.

I don't really have any more interesting laboratory test results. I only had general tests and they were mostly good even in acute phase. I wanted to write about them anyway and about my more peculiar symptoms (like recurrent chest pain), but I haven't had time so far. I will put it under the medical test results thread in one block maybe in a few weeks.

There are many thought-provoking elements here. Thank you for taking the time to write your reflections at length. Some remarks though.

As for me, I don't have any pain in the rectum area (apart from haemorrhoids sometimes). Codein (soft morphine) and Tramadol, which act through mu-opioid receptors, have a positive effect, as well as Paracetamol. So I would not be concerned by your theory if it were true.

I also have Gilbert's syndrome and never had any problem with Paracetamol, so I wonder if you could try it at low dose (300 to 500 mg, timed after orgasm, are sufficient for me), in order to test your theory.
Same with codein, maybe. In a previous thread you mentioned that you had good results with a mu-opioid antagonist, Low-dose Naltrexone, but I've read that LDN could also stimulate the endogenous production of endorphins, so I'm not sure that you can draw definitive conclusions on your reaction to opioids without trying them.

Most importantly, I don't understand the link between arousal or orgasm and the production of anandamide. Would it be through the Arachidonic Acid pathway highlighted by nanna1 in his first POIS theory ?

I haven't had time to check the symptoms for other types of POISers, but you may have some kind of withdrawal type POIS. I think it may be possible that you have a really low level of some kind of similar endogenous opioid or cannabinoid and it unbalances homeostasis. As to how it would relate to sexual activity I am even more unsure. Maybe during orgasm you lose even that small amount you have and precipitate symptoms or it actually increases, but it gets lower again and causes withdrawal until a new balance is reached. The time of onset of symptoms could also indicate a slow or fast reaction, although I have elevated symptoms even before O. But a theory is only a theory until proved and has to be tested out even if it may sound sound at first even if it is mine. You may give a try to capsaicin too if you haven't already. If I remember well it might even have some weak agonistic effect on cannabinoid receptors too. It can possibly lower cancer chance if you have a low anandamide level by chance. You could also try eating my blacklist foods, although I haven't figured it out why they enhance my POIS.
Three days ago I didn't even know that paracetamol was indicated in my disease. I will definitely give it a try to see how symptoms are effected.
Unfortunately I couldn't try naltrexone as of yet. I only said that when I had serotonin deprivation
syndrome all my POIS symptoms disappeared and I had very similar side effects. Serotonin definitely has something to do with my disease. Taking a moderate dose of tryptophan helps me, but at a high dose I develop a transient orthostatic intolerance and some POIS symptoms can still be felt.
At one point I thought I might have a low level of N?arachidonoyl?serotonin (AA?5?HT), but just now I can't recall why. AA-5-HT has an agonistic effect on cannabinoid receptors, but antagonistic effect on TRPV1 receptors. I have also just realized that it inhibits FAAH that leads to an increased AEA level. This might just explain why I experience some kind of dual effect with serotonin, but its positive effects still outweigh its negative ones.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0707145
Now we at least know that AEA can be found in the seminal plasma in relatively high amounts even in healthy persons. Even if you don't have any problems with AEA it might still set of a cascade of events  at O as its activity is tightly linked to other endocannabinoids like NADA, AA?5?HT, 2-AG, PEA, etc. and a malfunction in those would be revealed.
For your last question I can't answer as of yet as I am only beginning to consider its implication for myself. I will try out as many of nanna1's recommendations as I can although it will take a lot of time.

So what then could be the root cause that those chemicals which are in excess which then cause POIS and the background symptoms have been present in the first place and how could we stabilize this underlying imbalance that causes the POIS and the background symptoms?

I too often feel weird kinds of warmth and itchiness and other sensations throughout my body and some times I have had warm burning stools and I often feel like something is inhibiting my body as in some microbe types or something like that.

Also in relation to this theory:

What could have made my POIS disappear when I had a cold in 2020 February? I had two orgasms and one nocturnal emission and zero brain fog, vision changes, motor changes, mental processing speed slowdown and I felt as if the post-orgasmic blood flow and overall warmth sensation was different and I felt more pleasure in the middle deeper area of the genitals which I have never ever felt when I have had POIS so that could mean there is some link this is the only time I have EVER had no POIS symptoms other than abstinence, please tell me what do you think could be involved or causing this POIS free effect?

I don't even know if I have primary or secondary POIS. I think I first masturbated at the age of 11 and I  am sure I had IBS symptoms when I was 13. It doesn't mean I didn't have other POIS symptoms from the first time, but I might thought at the time that it was a normal issue. I was in high school when I realized that it has to do with masturbation and kept it a secret even from my relatives as one normally doesn't speak of such things. I always wondered if it was genetic or if it was somehow my fault. Around the age of 13 I masturbated quite a lot as there were days (not every) when I did it 5-6 times a day. Also someone one the forum mentioned that he developed POIS (I am not sure which type) in a period, when he consumed a lot of cannabis and had a lot of sex too. It might have been the case with me too. Of course I didn't consume cannabis, but normal enhancing foods might had had a similar effect and I might had been susceptible to developing POIS for all I know. Nonetheless even before the age of 11 I was quite a euphoric kid (Isn't everyone?) and showed some slight autistic behavior too. I also had a left testicular hydrocele when I was a few years old and had a minor surgery. It might not has to do anything with POIS, but it might have been present in its chronic phase even then without me realizing it.

About the other issue I generally I also don't really feel any pain either. I think the best way to put it is like imagine you eat a small amount of hot paprika or chilli pepper every time you eat and you would feel about the same during excretion. I don't even have severe pain anymore. It usually happened when I ate some enhancing foods (even paprika without capsaicin) and had very acute POIS at the same time. Pain is usually mild or only a warm feeling is felt or an ichyness occurs. Anandamide is 20-fold less potent than capsaicin, so even a mild burning feeling would mean that it has to be present in really great amounts.
I think you might have a similar POIS as mine.

I might have had reduced POIS during some illness, but I only heard about such a possibility a short while ago so I am not sure. One usually doesn't masturbate during an illness anyway so POIS would lower likewise. I think I had some extended illnesses (usually tonsillitis) when masturbating brought a relapse in subsiding disease too.
You might still be right, but I can only give you theories and nothing definite.
You could consider capsaicin and anandamide as they both seem to have proinflammatory and antiinflammatory effects to. This could have implications, but I am really not well versed in this regard.
You could also consider COVID-19 where they found that arachidonic acid may have a protective role against the virus. I was also wondering about sphingolipids, because it seems that AEA increases its production through ceramid production, but their level seems to be low in both CFS and COVID-19. Actually I haven't had the time to read the full article so you should check for yourself if you are interested. The same goes for cholesterol as anandamide can lower its level and maybe it can lower coagulation too. Anandamide could be the miracle cure for COVID-19 and the cause of postcovid at the same time for all I know and I really don't know.
Some POISers had mild symptoms during COVID-19, but I just don't know which type of POIS they have and it might be that some POIS types are very susceptible to it, so be really careful nonetheless.
And even if you are really resistant to it you might just be really unlucky and still die.
So even if you check everything out you won't know for sure, but theories can always be formulated.

In the meanwhile I have just found this:
Anandamide can be eliminated with polymixin B.
https://link.springer.com/article/10.1007/s00540-005-0366-5
It is not a cure of course, but maybe a possible treatment.

By the way I dropped out of university (due to my illness) and work as a kind of part time janitor and you shouldn't expect a very professional advice from a janitor I think.

I am also sorry about the apostrophe. I just don't know what to do besides retyping all of them. I usually write my text in office and then copy-paste, but it seems that it results in an error.

I had three orgasms while I was sick with that cold and I did not get POIS back then, there was zero brainfog and other cognitive and muscular and neurological symptoms afterwards I could literally function and the symptomless state remained once I healed but when I orgasmed after healing from the cold the symptoms INSTANTLY came back on FULL FORCE so being sick with that cold or for some other reason during those few days I had three POIS free orgasms.

And it was not simply that I already felt bad due to being sick or that I was more relaxed due to being focused on healing from cold the difference between symptom and symptomless state is like night and day when I have POIS I sometimes feel like I am half asleep and every text and everything is hard to comprehend I often look at items and I know they are there but there is like a delay towards remembering their names and such

[Progecitor]

I was quite tired last night so I have missed some things.
Most importantly AEA is also produced in many other organs. It might be that I have a high systemic level of it anyway and that is why I can perceive POIS symptoms even in chronic phase. The acute onset creates a superposition of concentration increase. What I don't get is why its production is up-regulated in the following days and this also doesn't go well with any withdrawal hypothesis.

Although there are some facts that may implicate that covid-19 would be weaker for us, but other things like a low testosterone as a risk factor or similar medicine working (like naltrexone being effective) may implicate othwerwise and researchers might be wrong about arachidonic acid too.
It might still be possible that covid-19 upregulates systemic anandamide production, which could lead to a postcovid state. We know for a fact from the Scottish woman's case that anandamide can lead to similar memory problems, but she also had FAAH out. From this it seems that some symptoms like brain fog are a result of its break down products.
I usually have brain fog and ocular photophobia in the morning and by evening my mind tends to clear up somewhat. I also tend to have a burning urine in the evenings. From this it may seem that AEA is highest in the evenings and breaks down during sleeping and I have a higher level of its by-products in the morning.

As I have talked a lot about POIS types I have to write about my symptoms so you can relate.
I think I have developed almost all symptoms of POIS at some point. In the beginning I often had a feverish feeling and was prone to IBS-D. This might have been because I hadn't eaten enough as my POIS seems to be accompanied with a serious energy expenditure. I was probably more prone to dysbacteriosis then, but it can't be proven in my case anymore. As to my current symptoms:
- The burning sensation of excretion I said before. After O I tend to have IBS-C (not by definition).
- Hypothermia or at least a perception of it after the heat of O passes. It is also noticeable at acute-chronic phase turnover after which I don't really feel cold anymore.
- Some kind of mild rhinitis is present all the time. The phlegm often contains some blood. My nose is often dry. A burning sensation can often be felt in the nose. Interestingly taking tryptophan or medicinal mushrooms (probably apigenin) makes this go away, but I also tend to sneeze more often, because of them.
- I hardly ever cough, but after talking more then one hour I usually develop a sore throat. I can have some coughing sprees too when I do a lot of physical work.
- Ocular photophobia: It occurs in the mornings. I can't keep my eyes open in the light as I feel as it is burning my eyes out. If I try to force them open I often sneeze. I don't have a skin light sensitivity.
- Red eye symptom: I often have a blurry vision linked to brain fog. I am also short sighted with about -3.0 and -4.0 diopter. My sight began to deteriorate around the time I had began masturbating, so there might be a link, but not necessarily. At acute onset I can have quite red eyes. It doesn't mean I have full-blown red eyes, but veins seem to leak. It might be due to vasodialation and/or irritation. This symptom can change really fast. It looks like my eye is constantly regenerating, but it can't always keep up with deterioration. In chronic phase my eyes can be really white, but as a low grade POIS is present it can return to some degree intermittently. I have found that tryptophan is very good at reducing this symptom.
- Skin problems: I only have mild skin symptoms. Some slight red dots appear on the chest after O. In the first few days after bathing and drying myself with a towel I can get a very itchy skin for a short time or until dressed. I often have some acne after O even if I have a shower, but it might be normal for the skin to become more oily after O. Very rarely I can develop a really painful red rash besides the anus when I sweat and work a really lot, but with cleaning and rest it disappears by next day.
- Increased hunger right after O: I just have to eat anything even when my stomach is full. I also have a similar experience by eating apple in the chronic phase. I also can't get rid of biting my nails unconsciously because of this and I might be more susceptible to pathogens, although it also seems that they can't really live within me.
- Cognitive problems: I have typical mind fog which is usually strongest in the morning, but can still be present in the evening. Blurry vision and decreased cognition are tightly linked. The more acute POIS is the less I can focus. I can have a psychogenic nausea from any mental activity during a very acute phase. I can usually tolerate passive activity (like watching TV) better then active activity (like reading or playing video games) even if it is fun. I have short term memory problems like forgetting things I have been just told or having a complete block down when speaking about something and I often can't recall words I want to say. I don't seem to have a problem with long term memory otherwise I wouldn't be able to write in English. Actually if I am reminded (like next day) I can even recall a short term memory, so it seems that it is all about the inability to recall short or long term memories. In chronic phase I can recall a lot more things and I can speak much more fluently. I also seem to be much more creative then. I don't know much about this stuff, but there is a distinction of episodic memory related to detail. I often noticed that when I read a book in chronic phase I remembered the details quite vividly, but after an O it is like I had an amnesia in episodic memory. I can still roughly remember what happened, but I simply can't remember the details and they don't really come back even in the next chronic phase unless I learned them.
I also found that mental activity can have a lower, but similar effect as tryptophan, and it is no wonder as it actually increases with both mental and physical activity.
- Muscle fatigue: General low-grade muscle fatigue. I can usually overcome it with willpower, but it still hurts while working. The lower leg doesn't really hurt that's why I can stand alright. The thigh hurts more especially when going upstairs. I also feel a weaker pain in my arm, but it is only a problem when I want to lift a heavier weight as even when I develop muscles I simply can't lift things due to increasing pain. It is so good to sit down after work that I don't even want to stand up for at least an hour. I found that applying menthol balsam can really regenerate it by next day, but with physical activity it soon comes back. Physical activity seems to have a dual effect as in some regard it makes my symptoms stronger, but it can also clear up my mind. With a short physical activity red eye problems can get better, but after a while it can even get worse due to exertion.
- Nodules in the breast: I don't even know when I developed this, but I had them for years and they are present almost all the time. After acute POIS onset larger nodules can be felt in the breast tissue. They are mildly painful to the touch. They get smaller as POIS vanes, but can still be present in chronic phase. They are certainly not malignant.
- Periodic chest pain: I only have this symptom from my early 20th of age. I think it has a connection with breast nodules as pain usually develops beneath them. This most often occurs right after O and when I manage my POIS badly like eating undesirable food. It is usually present for a few days.
The pain can be very severe. I can lie in the bed without feeling any pain, but for the slightest of movement it feels like being stabbed for a short moment. I think it might be partly because of some physical tension, but it might be some immunological thing too. It can appear on either sides or at both sometimes and it can also go from one side (it can disappear) to the other. At a moderate episode I was at the pediatric clinic and ECG proved negative and chest X-ray also proved negative so it is not apparently a pulmonitis or at least it is not an apparent pulmonitis. Blood test was rather normal and only creatine phosphokinase (CPK) was high with CPK: 1032 IU/L (24-190). CPK was good in other blood tests where it was measured. It might be an allergic case of extrapleural interstitial liquid without pulmonitis, but I might be wrong. I have bought N-Acetyl cysteine (NAC) [600 mg] a few month ago as I thought it might help with this symptom, but I have controversial experiences with it. I think it might make this symptom occur more often or can extend it although I am still unsure. I wouldn't have mentioned this yet, but someone here who had the coronavirus said that NAC made his symptoms worse. So I can't say for sure if it is bad, but be very careful with it.
It might actually really cleans the lungs, but also makes it more susceptible to allergens in the process.
Somewhat contrary to this when riding a bike (weak exertion) and breathing a lot of fresh air symptoms can get better. I also noticed that charcoal can help somewhat while coffee (black list foods too, but coffee did this many times so I am sure of it) can reintensify pain.
- Periodic kidney pain: at a time it occurred once or twice a year and lasted about two days. Usually the site of the kidney was in pain. I haven't had a medical check-up for this so I don't know more. I am sure this developed due to sit-ups, which can increase my disease the most. I think I even had a pancreatitis once for a few days due to this. When I have a muscle fever I feel really bad for days. At the time I thought it was due to some kind of lactic acidosis, but I am really not sure at this point. I really think that anandamide has something to do with lactic acid, but I haven't had time to check this out. I haven't had this symptom since I stopped doing sit-ups and it was years ago.
Other considerations:
- Chronic sleep deprivation generally makes me feel more ill.
- After acute sleep deprivation (about 22 hours) I develop a kind of superPOIS state. I begin feeling very unwell. I get a constant tingling sensation in my belly. My anus is constantly itching. At a time I also felt like freezing, although it was a warm summer day. It was hard to stop the shaking under the blanket, but a good sleep solved the problem every time. I only had this state a few times and not in the last ten years, because I am not stupid to stay awake to wait for it anymore. In reflection it might be because of an AEA hyper concentration. My body might not be able to break it down fast enough if I don't sleep. I should recheck this state, but I can't really get myself to do it.

The following may not have a relation to POIS:
- Sensory neuropathy: Around 2010 I had about 4 or 5 episodes (with a few month to a year in between) of neuropathic pain which had lasted for about one or two month. It either started from my big toes on both of my legs and day by day slowly crawled up to my waist. Or it started from the fingers on one of my arm and crawled to my chest. It felt like constantly being stabbed by tiny needles on the skin surface which was a hellish pain without seeming of an end. I could move, but I didn't want to stand on any of my legs because of the pain or couldn't easily hold a pen when it was my arm. There was a time when I was lying in the bed in the morning when it was warm under the blanket, but I felt like freezing. It seems my receptors had ran haywire on my skin. The first time was the worst though as I thought that it would never go away. At the first episode I went to see the doctor after a week where the GP prescribed meloxicam, which did nothing to the pain. I also went to Rheumatology where they told me I have no muscle, but they didn't give me the correct diagnosis (it was dorsalgia and muscle pain). As the pain somehow disappeared on its own after quite a few weeks I didn't even seek medical knowledge in the following episodes. I was quite disappointed in doctors by this time. I have only found out that I had actually had sensory neuropathic pain a few years ago while I was searching for POIS. I really have to question how competent they were at Rheumatology or if they just didn't want to bother with me. Fortunately this kind of pain haven't returned for years, but even if it had now I at least know its name.
I had some O during these episodes and it had never change the normal POIS episode. Still I think the actual initiation of the episodes were linked to times when I did sit-ups more often, and since I realized this I have never done sit-ups anymore. It really might have been the nerves in my backbone in this case, but who knows for sure.
- Enlarged lymph nodes on the backside of the neck somewhat under the ears. I developed this a few years ago. Once or a few times in a year either of them can get inflammed for a few days, but then the pain disappears. It doesn't react to acute phase, but it seems somewhat similar to the chest pain.
- Epigastrial discomfort: It also only developed a few years ago. It might have been the result of eating too much all the time. I often felt my stomach was full even when I was hungry. A mild pain was present almost all the time. I didn't have a medical check-up for this but I also never had reflux.
- Ass muscle pain/inflammation: It also developed only a few years ago. The origin of the pain is deep in the muscle somewhere close to the rectum, but it doesn't seem I can feel any nodules there. It resembles very much to the chest pain. It usually lasts a few days. The pain can be present on only one side, but can also move to the other. It has the same stabbing kind of pain with movement. Only a kind of inflammation can be felt when I am not in motion. As pain becomes very severe I practically become lame and can hardly move. Now the most perplexing thing in this regard is that this symptom most often occurs at the beginning of the chronic phase and the only really thing that can actually stop its build-up is having a release. If I don't release just masturbate it can enhance the pain. Even O doesn't make it regress right away, but it seems to be a turning point in its course. Two years ago I very often had this pain and interestingly chest pain occurred less often although I masturbated with about the same frequency. I also did quite a lot of physical work at the time, but mere acute physical work can't seem to be able to initiate this symptom. Fortunately I barely had this symptom this year although chest pain frequency increased. So its either a decreased workload or the other thing I suspect is taking a tryptophan supplementation. My epigastrial discomfort also disappeared after about three years and I really suspect tryptophan supplementation. Interestingly tryptophan doesn’t seem to have a bad effect on chest pain. So I didn't prove anything and they are merely guesses, but if you have similar problems by chance you could give tryptophan a go to see if it does anything. Just to be frank about the same time I was also taking beta-alanine and alpha lipoic acid in greater doses. I took beta-alanine (2 x 2 per day with 1g per pill for 2 months) to see if it would increase muscle carnosine and alleviate pain. I am quite sure it did nothing to POIS and muscle fatigue didn't change and the only side effect was a very similar pain I had during sensory neuropathy, but this was only transient and not so vast. Alpha lipoic acid (2 x 1 daily with 250 mg per pill) really had some cleaning effect at the beginning so it might have been that too. I took it for 2 months too, but I didn't perceive much effect on POIS. I had less urination problems and it was burning a bit less so it was somewhat effective, but not to a great degree.

I think I will put off POIS research for a few days as I have been reading medical articles non-stop for a week now and my mind is a jumble. I also have about 90 chrome pages open all the time. Maybe I need to flush out all of this new information with an O just to make a clearer picture.

[Progecitor]

I am sorry I haven't even checked out some most basic information in the hurry to share my findings.
It is true that CBD can block the effect of THC, which I have never consumed, at the CB1 receptor, but it doesn't itself bind to the CB1R and CB2R, furthermore it also inhibits FAAH and this way it actually increases the level of anandamide of which I want to avoid as it really activates CB1 and TRPV1. Also CBD also activates TRPV1 and thus it would only increase the whole effect of anandamide sepsis.
CBD might be ideal for someone who has a low andandamide level, but it would only enhance my type of POIS. Nevertheless I will still try it when I can afford it, but I don't have high hopes for it.
https://www.alchimiaweb.com/blogfr/wp-content/uploads/2015/11/CBDiary21-CBD-How-It-Works.pdf

I have been thinking about other potential medications and they may also have problems such as the route of appliance, because anandamide is produced at many sites in the body and it may be that its production is only increased at the prostate. So taking them orally may not have the desired effect and use in the form of a suppository would be desirable. For example Polymixin B (PMX) might eliminate anandamide, but it is also a potent antibiotic and could have a really bad effect on the gut flora.

I have also recalled some other info about my symptoms:
- Cognitive problems: When brain fog is heavy in the morning (usually until late afternoon) my train of thoughts often stops completely. I just gaze stupidly at the world and can only have the most primal of thoughts. I actually see that others see that I am stupid, but I just can't do anything about it and it is frustrating.
- Urinary problems: I don't have a problem with holding the urine, but I have a serious problem with the urge of urination. I don't really have to go peeing very frequently, but the urge comes in a few hours. If I don't urinate my symptoms are enhanced. If I urinate the volume is usually small, so it is not like my bladder can't hold any more, but I think AEA becomes concentrated and begins to irritate the nerves in the bladder. The kidneys probably also reach a threshold where they can force AEA into the urine and so its level begins to elevate in my whole body aggravating symptoms. It is often a bit hard to let go as at the end of the penis it actually creates a slight pain which wants to stop my body from letting go. I could sleep through a night when I was younger, but since a few years ago (when I was 28-29) I almost always wake up at night sometimes very precisely in 6 hours from going to sleep. Although when I am in the chronic phase I can often sleep through the night without waking up.
- Slight tachycardia: My blood pressure seems to be normal usually, but it seems I can have some problems with my pulse. There are times when I suddenly wake up at night even when I didn't have any bad dreams. My tinnitus can be especially loud. When measuring it the blood pressure seems to be good, but pulse can be 90-100. After I go and urinate (decrease AEA) and drink a bit of water I can go to bed again and slowly I feel relaxed again.
- Conjunctivitis: I am not sure the medical terms I use are correct, but I often have dry eyes which is of course in some relation to red eyes (maybe uveitis). This symptom can occur anytime and especially when I am in front of the monitor. It also tends to increase at late night when I am getting tired. If I still force them I tend to have more red I symptoms. Interestingly taking the tryptophan supplementation can increase this symptom even though it tends to reduce red eye symptom. When I take a high dose my eyes are dry which feels like a tension and lasts throughout the night. Tryptophan might be able to overcome the vasodilatating effect of AEA (through NO), but not its irritating effect.
Last time I bought a monitor I opted for a blue light filter capable office monitor instead of a gaming one and it noticeably helped my eye problems although it didn't solve them of course.
- Sleeping problems: Often I can only get myself to sleep when I am on my belly. At the first time I heard about COVID-19 patients being better lying on their belly-side I immediately associated to my disease and always thought that there must be an association between the two and now it seems especially likely.

[Iwillbeatthis]

- Sleeping problems: Often I can only get myself to sleep when I am on my belly. At the first time I heard about COVID-19 patients being better lying on their belly-side I immediately associated to my disease and always thought that there must be an association between the two and now it seems especially likely.

I go through long periods where this also happens to me, I feel like sleeping on your belly isn't a healthy position to sleep in.

I don't have CFS but once in a while I get hit with extreme tiredness sometimes with a headache and I wake up from the nap with completely blood shoot eyes every-time, I'm not sure why this is.

[Progecitor]

In my previous research I have also identified some other diseases that might have a close relation to POIS, although in a weaker form. These are of course not facts, just mere possibilities and maybe considered as sub-POIS phenomena:
- Exercise induced allergy: If AEA really plays a role in runner's high, then it might just be the link to it. More severe cases might be mediated by other factors (e.g. food). I don't deny that AEA has more pros than cons, but not in very high concentrations.
- Honeymoon rhinitis: Although it is considered a woman's ail, this just might be the reason why there are many more males with POIS. The prostatic tissue in woman is (maybe) closer to the vagina. Common medical knowledge states, that it is due to bacterial infection or dysbacteriosis, but there are cases when bacteria cannot be found. I think my idea of a high concentration of AEA leading to dysfermentation and dysbacteriosis might explain this much better. I don't even know why they have never tried to identify a metabolite for it if they knew that microbes might not be the only cause.
- Chronic nonbacterial prostatitis (chronic pelvic pain syndrome): Same as before, although I haven't checked if it is related to sexual activity or flu-like symptoms at all.
- Sex induced headache: It would be worth to check if it is really the only symptom and nothing else.
- ACHOO or photic sneeze reflex: Photophobia and sneezing seems to be directly related. I don't say that ACHOO is caused by POIS, but it is evident to me that POIS directly causes ACHOO in me in an intensity dependent manner, which can be further aggravated with specific food (see my list).
- Increasing incidence of allergic cases (hygienic hypothesis) generally, an increase of red eye symptoms (of course screen gazing is the main factor) and an itchy anus (especially males). It might be a consequence of an increased sexual liberalism worldwide. This supposition might generate a lot of debate, but AEA has a lot of beneficial effects too, so I don't think that sexual activity is a bad thing on its own and done in moderation of course. I also don't want to contradict the hygienic hypothesis, which is probably true on its own. I just want to point out that other factors might also be at play.
- Slight cognitive impairment after childbirth: It is a far-fetched theory, but it might be that AEA is slightly up-regulated after childbirth and mothers become slightly defocused and aphasic, but also more sociable and relaxed.
- Problems related to cannabinoid and opioid use, although they might not be related directly to sexual activity or AEA. For example: cannabinoid hyperemesis syndrome and opioid withdrawal, etc.
Less likely to be directly related:
- ME/CFS: Although sexual activity is not indicated as a factor (at least someone mentioned on this site and I haven't checked really), but a systemic up-regulation of AEA still can't be ruled out in my opinion.
- Post-covid or long-hauler covid: Same as CFS and the effect of sexual activity on COVID-19 is really unknown at this point.
- Auto brewery syndrome: I had negative results of rapid alcoholic tests even in acute POIS. So although I don't think that this state is directly related to POIS, but the appearance of Klebsiella sp. was also indicated in its course and some symptoms may resemble a bit. It might be that the only common thing is dysbacteriosis due to high substrate concentration.
- IBS, leaky gut syndrome, lactose intolerance, celiac disease might have some similar symptoms due to dysbacteriosis and probably a whole lot more of diseases where dysbacteriosis occurs, but the direct involvement of AEA is not likely.

The term OIH is actually used for two directly related phenomenon, which is opioid induced hypogonadism and opioid induced hyperalgesia.
"There is increasing evidence suggesting that testosteron (TST) in those patients with OIH can reduce hyperalgesia, improve sexual desire, body composition, and aspects of quality of life (QoL) (Basaria et al., 2015)."
"These findings are consistent with published animal studies that highlighted male gonadal hormones can play a key role in inhibiting the behavioral responses to repeated nociceptive stimulation and suggested that the lower incidence of chronic pain syndromes in male rats could be caused by the presence of these hormones"
https://journals.sagepub.com/doi/full/10.1177/1557988316672396

Anandamide can be high in fibromyalgia.
https://www.sciencedirect.com/science/article/abs/pii/S0306453008000590

Muon! If you haven't found this already you might be interested in this article as it seems to be related to your relatives at least if my theory holds true.
"All the females who got health problems felt better during their pregnancies and felt worse during their menstrual cycle."
AEA is low during pregnancy, but is high during menstruation, especially in the follicular phase.
The low levels in postmenopausal women and the high levels in the follicular phase suggest that steroid hormones primarily regulate AEA levels, with estradiol increasing the levels and progesterone suppressing them. The effect of progesterone could result from regulation of the degradation of peripheral AEA by peripheral blood mononuclear cells given that the levels of FAAH, the principal enzyme involved in AEA degradation, in these cells are regulated by progesterone. The induction of high AEA levels by estradiol could be mediated by its effect upon endothelial cells given that it has been reported that estradiol increases the release of AEA from these cells into the circulation.
https://academic.oup.com/jcem/article/89/11/5482/2844400?login=true

Sleep deprivation in control animals can significantly increase testosterone, but also significantly reduces FAAH activity, which of course increases AEA.
https://www.sciencedirect.com/science/article/abs/pii/S0304394020305243

Anandamide can induce photophobia in animal tests:
https://www.liebertpub.com/doi/10.1089/jop.2011.0049

So I might be wrong about NAC or POIS is just that peculiar. Also it seems that taking paracetamol might be a risk during infection.
Among them one by De Flora et al. (2020)-who published pioneer studies on the pharmacological relevance of the GSH precursor N-acetylcysteine (NAC) in the 80s and 90s—stresses the need for thiols supplementation for both the prevention and treatment of COVID-19.
Higher levels of GSH have been associated with better individual’s responsiveness to viral infections.
Paracetamol (PAC) and its metabolites decrease GSH levels, also when given at relatively low doses in healthy volunteers.
Although the drop in hepatic or renal GSH is the most toxicologically relevant interaction (see also below), plasma GSH, free cysteine (Burgunder et al., 1989), and antioxidant capacity (Nuttall et al., 2003) were significantly reduced after a single 2 g PAC administration or 14 days of therapeutic doses of PAC in human volunteers, respectively; 3 g PAC for 14 days in older people led to a significant reduction of sulfur amino acids (Pujos-Guillot et al., 2012). It is of worth that PAC plasma levels can even increase above the expected concentrations exacerbating thiol consumption under conditions of gut dysbiosis (Mukhtar et al., 2019), another common status in COVID-19 at risk population (Aktas and Aslim, 2020). Furthermore, clinically attainable concentrations of PAC have been shown to decrease in vitro intracellular GSH in human pulmonary macrophages, type II pneumocytes, and lymphocytes (Estévez et al., 1994; Dimova et al., 2005). Notably, the depletion of GSH in airway mucosa is considered as the most biologically plausible mechanism of the established epidemiologic association between PAC use and asthma prevalence/severity in children and adults (Shaheen et al., 2000; McBride, 2011), implicitly suggesting that GSH depletion may take place also in other clinical settings.
Oxidized PAC-quinone imine metabolites have also been shown to form GSH-conjugates which inhibit glutathione reductase (GR): the decreased activity of GR hampers the detoxification and antioxidant capacity of the GSH-GSSG cycle, further aggravating the pro-oxidative status in the cell.
The production of quinone imine metabolite is the primary responsible for PAC liver and kidney toxicity. Ninety-seven percent of drug-induced acute liver failure have been ascribed to PAC; liver enzyme alterations are very frequent in PAC treated patients, even at routine dosage; the maintenance of patients’ liver and kidney function is obviously important for the body’s ability to react to infections, including COVID-19.
https://www.frontiersin.org/articles/10.3389/fphar.2020.579944/full

Anandamide and arachidonic acid seems to be ACE2 expression agonists, which theoretically have a protective role in COVID-19 infection.
ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 reduces angiotensin II levels. Thus, ACE2 plays a protective role in the respiratory system, cardiovascular system, and kidneys. However, SARS-CoV-2 infection induces a reduction in ACE2 levels and disrupts its protective function in the respiratory and cardiovascular systems, as well as other important organs. Patients diagnosed with COVID-19 rapidly deteriorate to severe or critical conditions. Therefore, taking inhibitory drugs against SARS-CoV-2 or activating ACE2 may be potential therapeutic strategies for treatment of this infectious disease. Thus, there is an immediate need to identify drugs that could improve multi-organ deterioration in severe or critical COVID-19 patients.
Among effective ACE2 agonists were:
- OMDM-2 (Anandamide uptake inhibitor)
- Eicosatetraynoic-acid (Cyclooxygenase inhibitor, Arachidonic acid uptake inhibitor)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378642/

While having a high AEA and arachidonic acid level seems to have a protective role, it is rather contradictory that paracetamol (through FAAH inhibition also increasing AEA) would have a detrimental effect, although it is supposed to be due to glutathione (GSH) depletion.

Also some preliminary information on supplements and medicines:
I tried paracetamol (Rubophen 500mg) once. I only dared with a lower those, so I took about a third of a tablet (about 200mg), but it still gave me a reaction. In less that an hour I had a really hot flash like having a fever, but it only lasted for about half an hour. About 2 hours later (I will measure more precisely next time) I had a severe flatulence with burning farts (I can't put it any more nicely). It was not timed to O, but on a 4th day of acute phase.
I had a similar experience with taurine, but I only tried it a few times [1 g]. Last time I took 2 g I also had a few hours of heart-ache.
Heart-ache is not a symptom of my POIS, but there are a few things that can give me a heart-ache.
One is fish oil [the one I used contained 1000 mg with 490 mg omega-3 (EPA: 110 mg, DHA: 100 mg), vitamin-A 800 mcg and vitamin D 5 mcg]. I took 1-2 a day, but even taking one could result in a day's of heart-ache, which lasted more if I took more. I took this 5 years ago and not in relation of POIS, so I might not be very precise. I mention this because I want to test out EPA in the near future and I just hope it won't have a similar effect.
Another thing that can give me a heart-ache is Aspirin protect [acetylsalicylic acid (ASA) 100 mg] and often even if I take only one.
Somewhat contrary to this if I develop a heart-ache by eating high fat foods (like beacon) and then having an O can make it disappear very promptly even if I had it for hours. It seems as if POIS is really burning through me.
I also bought a product named Apigenin, but only then do I realize that it actually contains other things too [Taurin 800 mg, Green Tea 200 mg, Apigenin 24,5 mg]. I also tried it and it seems that it may even enhance problems and I think it may be due to taurin, but I will test it further.
I also had some medicinal fungal pills left in the fridge. I tested them a bit more and it seems that testosterone can ameliorate its bad effects, so it turned out to be quite good. What I also tried was to take it together with chamomile tea and its good effects were even more enhanced. It caused a bit of flatulence by next day, but at least it was not the burning kind.
I tried Sulforaphane [400 mcg] a few times and I don't think it really does anything noticeable. At one time it made quite a flatulence, but I don't think it enhanced or reduced the burning feeling. I also found somewhere that it can up-regulate mu-opioid receptor expression, but I am not sure it can help me. I will test it some further of course.
I have recently tried MSM [1g] and I think I feel a bit better, but it might not be a POIS thing and I still need to test it further.

[Progecitor]

So what then could be the root cause that those chemicals which are in excess which then cause POIS and the background symptoms have been present in the first place and how could we stabilize this underlying imbalance that causes the POIS and the background symptoms?

I too often feel weird kinds of warmth and itchiness and other sensations throughout my body and some times I have had warm burning stools and I often feel like something is inhibiting my body as in some microbe types or something like that.

Also in relation to this theory:

What could have made my POIS disappear when I had a cold in 2020 February? I had two orgasms and one nocturnal emission and zero brain fog, vision changes, motor changes, mental processing speed slowdown and I felt as if the post-orgasmic blood flow and overall warmth sensation was different and I felt more pleasure in the middle deeper area of the genitals which I have never ever felt when I have had POIS so that could mean there is some link this is the only time I have EVER had no POIS symptoms other than abstinence, please tell me what do you think could be involved or causing this POIS free effect?

So I have managed to formulate a theory to your question, but of course it is nothing proved.
If we take COVID-19 there is a plausibility that there is an up-regulation of anandamide (AEA) production in the body. There is a possibility that this is not even caused by the virus, but by the body itself, because it might be the best defense against this kind of threat. I often feel like POIS is burning through me and as it is caused by a capsaicin-like compound (AEA), it seems to be actually the case. Preliminary research showed that the most promising anti-covid natural compounds are curcumin, piperine and capsaicin as they can bind to the viral protease and induce a folding of the enzyme thus inactivating the virus (the research is still going on about this). As AEA and capsaicin has a very similar chemical structure it is not unreasonable to think that AEA would have a very similar effect on the virus. Capsaicin has been proven to have antibacterial and anti-viral capabilities, so AEA probably also has.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=covid+capsaicin&btnG=
(The first link is a PDF about it.)

Given that the two binds together not only the virus count would lower in the body, but AEA would also diminish resulting in lessened POIS symptoms. Now the problem seems that if the virus gets eliminated, sometimes the body may not realize this correctly and simply can't come down from this up-regulated state. As the virus totally disappears the heightened state becomes apparent resulting in an expression of post-covid syndrome, which could actually be a result of elevated systemic AEA production. If my insight is true than this is actually a highly universal defense mechanism of the body which also means that other pathogens could also increase its level during an infection. Others here also hypothesized that other viral or bacterial infections could lead to POIS development and especially if it happens in the urogenital region (e.g. tick bite in testicle). Someone also mentioned on the site that he had the most serious cases of POIS after a malarial infection, which implies that the infection further up-regulated AEA production as a universal defense mechanism.
It could also mean that in an early covid-19 state my black list foods could prove beneficial, especially capsaicin, as they might be able to ameliorate the viral infection without the body getting into an up-regulated state. If however an up-regulation happens these foods should be avoided at all costs as they could induce the cytokine storm that causes death.
As for why some antibiotics could either cause or reverse POIS is that they maybe able to switch the up-regulating or down-regulating switch in some cases. For example Polymixin B can eliminate AEA and this also means an indirect antagonistic effect on its receptors (CB1R, TRPV1, GPR55 and maybe others too). Other antibiotics may have similar yet unknown capabilities or they can actually get rid of an underlying infection which lets the immune system switch back on its own.

This makes me really worry as if this is true than getting a covid vaccine would lead to a systemic up-regulation of anandamide of which I have too much already. Although I have POIS symptoms even in the chronic state I still think that it is only due to its prostatic over-production as AEA can rather easily pass membranes and may constantly seep into the body and blood stream. So maybe I don't really have any FAAH or it is rather reduced at the prostate and AEA simply can't be broken down at the site. At other sites of the body however I still have a higher activity of FAAH, which reduces AEA so that I don't have a fatal sepsis of it.
Anyhow in case of a systemic up-regulation of AEA by a vaccine could even further raise this level and I might even die a similar death as if I had covid without actually having it. We should know if my theory is either true or false if many people begin to show low-grade symptoms of a post-covid state.
I have just found such a possibility although it is really far-fetched.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817408/
I know that it is a really strange example, but I also have nodules, enlarged lymph nodes in my breasts, which are very closely related to my actual POIS state.

However if my theory proves to be sound than an other implication would be that those who have a low AEA POIS could actually get cured.
However if they are really unlucky and catch covid-19, they may actually have a POIS turnover from a low AEA to a high AEA POIS or simply develop a general CFS or post-covid, but this is really an extraordinary speculation.
I am also not sure about similar medicine working in POIS and covid-19 and I don't even have any experience with them myself. As a possibility it could turn out to be the dividing line between early and late stage covid, just as what I suppose with foods. If so early stage medication in covid would exacerbate symptoms in POIS (my type), but late stage medication would be beneficial.
As a final word the contrary can also turn out to be the case or that AEA has nothing to do with the coronavirus and it is really just a theory until someone actually measures AEA levels in covid patients.
So I don't really have an answer to your question as I am by all means NOT a doctor and you either take it or leave it, it really only depends on you.
And I really must EMPHASIZE this as I don't want anyone's death on my conscience, because he or she thought that I am necessarily right and did something stupid (like not getting the vaccine).

[Progecitor]

Personal experiences:
A few other symptoms I forgot:
Headache: Of course I can also have headaches, but I can pretty well control the appearance of this symptom, so they don't pose such a threat anymore. At the beginning of my severe POIS development (around the age of 17, but I had symptoms beforehand too) I had some very serious headaches. At one time I clearly remember that I was lying in bed for two days as I had a very bad headache (unresponsive to painkillers) and sometime I opened the window to get some fresh air and then miraculously only an hour later there was hardly any pain. Since then I always try to get as much fresh air as I can and keep a window slightly open even during winter. I haven't really tested many painkillers, but Quarelin 400 mg metamizol sodium, 60 mg caffeine, 40 mg drotaverine hydrochloride can surely get rid of it and often even a half is enough if the pain is not severe. It is rather strange that it contains caffeine as drinking a coffee can often elevate (there are cases when it lowers it) a head-ache as well as my other symptoms. I suspect that other components play a role in this and caffeine just might be good. Another thing that can cause a headache is if I can't go to the toilet in the morning and have to do a lot of physical work. A headache that develops this way usually doesn't react well to painkillers and often only going to the toilet can solve the problem after witch the pain can slowly subside. Mainly this is the reason that I still keep drinking coffee in the morning, although it can surely cause red eye symptoms and enhance chest pain (probably more AEA), but can reduce brain-fog (probably less break-down products of AEA) and clear me out (reduces both AEA and by-products by my theory).
Other less frequent symptoms: transient joint pain (There was a time when I actually developed it for a few days or weeks while I was taking glucosamine-sulfate), transient muscle twitches (usually resolves with position change. I think it might be connected to the blood veins, but I was not even aware that this could be a POIS specific symptom and haven't really cared about it.)
Sleeping problems: I usually get quite tired right after O, but not to a degree that I can't stay awake, just that my body really desires it. I can have a disturbed sleep on the first sleep after an O, but on the following days I can usually rest quite well unless I wake up because of the urge to urinate or the loud tinnitus. What I also noticed that in acute POIS I don't really have any dreams. I am not exactly sure if I don't have them or just can't remember them. As chronic POIS follows I begin to have more dreams or at least I can remember them. The problem with vivid dreams is however that they can often be erotic and my unconscious ego tends to realize the consequences too late.
I also noticed that I can get a very refreshing sleep without a blanket even if I have a pajama on, but I can only do this in the summer when there is a relatively warm air, especially due to my hypothermia.
Chest pain: Actually it is rather lucky that I have never told anyone at my work place about my chest pain as I have it quite frequently. I can usually conceal it quite well and even in those cases I couldn't I always said it was only a heart-ache, because of a weak heart, so they don't suspect me of harboring tuberculosis or something. If I had really told about it to others I might have been in trouble due to the pandemic as I would have been suspected frequently even though I had this symptom for a decade now. It is not even like I was lying as even my relatives and my doctors had never believed it. Even at the one time my blood test showed something the doctor said it would go away. I knew that even without being told, but the problem is that it always returns too.

Things that enhance my POIS:
1. ejaculation: Make no mistake I have a chronic phase and O just enhaces it in my (s)experience.
2. sleep deprivation: either chronic or acute
3. diet: It doesn’t really matter what I eat I still have POIS, but some food can seriously enhance it.
4. physical and mental exertion: usually dual effect: some symptoms strengthen while others weaken.
5. medicine and supplementation: Can go both ways. Many things are under trial.

Psychologic effects that can enhance my POIS (probably due to parasympathetic enhancement):
- Having a cathartic experience while watching a good movie.
- Crying (sometimes because of my sorrow)
- Reading a lot has a dual effect (probably tryptophan)

What actually weakens my POIS is psychological stress, but only for a short time and it also doesn't make it disappear.
I can't even feel myself good even when I am relaxed! I just hate this disease to my guts!

Further research on anandamide (AEA)

I haven't even found this before, yet Polymixin B (PMX) seems to work in severe COVID-19, although it seems to be able to cause hyperpegmentation too as a rather serious side-effect besides kidney damage.
https://onlinelibrary.wiley.com/doi/full/10.1002/rcr2.679
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=+The+use+of+Polymyxin+B+Hemoperfusion+for+COVID-19&btnG=

AEA induces overeating.
https://link.springer.com/article/10.1007/s002130050953

A low AEA level has a role in Alzheimer's disease.
https://www.sciencedirect.com/science/article/abs/pii/S0197458011000844

FAAH enzyme expression is increased in Down's syndrome which probably leads to a low level of AEA, but it might also turn out to be actually high.
https://www.sciencedirect.com/science/article/abs/pii/S0306452207012924
Alzheimer’s disease patients showed that the expression of cannabinoid receptors of the CB2 type is induced in activated microglial cells while fatty acid amide hydrolase (FAAH) expression is increased in reactive astrocytes.
Well it might turn out that I have both high AEA and FAAH so it is hard to tell what is the truth without measuring it. So in regard to the new coronavirus article about poisoning astrocytes (see below) and taking into account that Down's syndrome is considered a real risk factor in COVID-19 infection anything can happen really.

A lower level of AEA can be found in Parkinson Disease (PD), although it can also increase due to some compensatory mechanism.
https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.28186
https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.23014

FAAH can be low (so AEA is probably high) in Posttraumatic Stress Disorder (PTSD) patients
https://tspace.library.utoronto.ca/handle/1807/103310

Higher AEA levels can be found in active celiac disease (CD). So a gluten free diet could lead to lower AEA for those whom this is a potentiating factor. This might be the case for "Going Less Crazy".
https://www.sciencedirect.com/science/article/abs/pii/S0955286311002233
Actually it seems to me that getting AEA POISoned is an additive mechanism. "Dredd" on the forum also claimed he only had POIS when he used cannabis, so it is logical to think that the exogenous cannabinoid added to an already relatively high endocannabinoid level, which in itself might not have been enough to induce noticeable symptoms, but together acute manifestation became expressed. If one is missing no symptoms appear or at least not in an easily perceptible manner.
Regarding this I also had a theory for a long time now that there is a kind of subPOIS or subchronic POIS manifestation, in which an acute onset might be as high than a chronic expression for me. In this case subPOISers would have sporadic symptom manifestations leading to everyday occurrences (e.g. headache) and they wouldn't even be able to realize that it was due to sexual activity. It may even turn out that it has a rather high incidence. So given this "Going Less Crazy" and "Dredd" are probably cases of such a subPOIS phenomenon. The only problem with this hypothesis is that fibromyalgic and PTSD patients also have elevated AEA, so an O in their case should lead to at least to a mild increase in their symptoms. So either they are not perceptive enough to sense this or an other explanation has to be found.
https://poiscenter.com/forums/index.php?topic=2589.msg25603#msg25603

Consuming flaxseed oil in milk emulsion can lead to FAAH upregulation resulting in lower AEA levels.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Effect+of+flaxseed+oil+supplementation+on+the+erythrocyte&btnG=

Sheep cheese rich in alpha-linolenic acid (ALA), conjugated linoleic acid (CLA) and vaccenic acid (VA) reduces anandamide.
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/sheep-cheese-naturally-enriched-in-linolenic-conjugated-linoleic-and-vaccenic-acids-improves-the-lipid-profile-and-reduces-anandamide-in-the-plasma-of-hypercholesterolaemic-subjects/2E51F7E3A3889E423E1982C90B4DF558

On the other hand another study claims that vaccenic acid actually raises AEA levels and this has an inflammation suppressing effect.
https://www.sciencedirect.com/science/article/pii/S0022227520354195

AEA may activate GPR55.
https://www.sciencedirect.com/science/article/pii/S0083672909810054

GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.
https://www.nature.com/articles/cr201160

NAE and NAPE are anti-inflammatory.
https://academic.oup.com/jb/article-abstract/145/1/43/879328

NAEs modulate mast cell activity.
https://www.pnas.org/content/92/8/3376.short

AEA causes vasodilatation in vitro and a brief vasoconstriction followed by prolonged depressor response in vivo. AEA has similar cardiovascular effects as THC.
https://www.sciencedirect.com/science/article/pii/S1347861319305432

A model of fibromyalgic pain and the effects of testosterone seem to be very well in line with POIS.
It had been long observed that high levels of Substance P can be found in fibromyalgic patients without  apparent inflammation.
Fibromyalgia is therefore best described as an inflamed nociceptive nervous system, distinctly different from various inflammatory states with(out) high WBC counts in peripheral tissues.
I think this is rather indicative of a capsaicin-like compound and they even measured high AEA levels. Why couldn't they make the connection?
As AEA is increased in both cases it could very well be the actual initiator of the pain insult seen in the figure.
One only has to put a high AEA level as an inducer of the (capsaicin-like) pain effect and the flow diagram is in the figure. A prolonged high level would lead to both testosterone and serotonin decrease. Aromatase activity leads to increased estradiol and opioid production which lowers pain treshold. In regard to my theory this whole loop would be kept running at an elevated state, because as soon as opioid level could decrease, the high level of AEA would induce pain again and prolong the loop.

As an alternative explanation opioid induced hyperalgesia (OIH) might also be an inducer of pain and would also lead to a self-preserving loop. From the first post we know that even a little amount of opioid is enough to fire up the cycle, of what O could very well provide.
Women have both a lower level of testosterone and serotonin which could act as a buffer and probably the reason FB is more common in them.

(I am sorry, but I haven't figured out how to insert the picture, so check out at the article's link. It is only a hypothetical model, but it seems really good to me.)
A. In normal individuals, a painful/stressful stimulus up-regulates Substance P in the nociceptive relay neurons and serotonin levels drop, consistent with a loss of feeling of well-being. Substance P has been found to stimulate aromatase, which would catalyze the conversion of testosterone to estradiol within the CNS, with subsequent upregulation of opiates and consequent dampening of pain. B. In fibromyalgia patients, deficient levels of testosterone are predicted to result in a "frustrated" cycle (due to lack of substrate) in which conversion of testosterone to estradiol is inadequate for induction of opiate-mediated dampening of nociceptive signals, resulting in abnormal chronic, diffuse, widespread pain. Estradiol, refers to 17-beta estradiol.
https://www.sciencedirect.com/science/article/pii/S1567576915002490


At least they have recently considered a possible role for the endocannabinoid system in fibromyalgia and it is to be researched in the near future. Interestingly naltrexone can improve fibromyalgia in some cases. It really seems like a POIS on a systemic level.
https://www.hindawi.com/journals/prm/2020/6541798/

I have also just visited the fibromyalgic forum and they seem to be worried about the vaccine too and based on this list it may be no wonder.
https://www.intellihub.com/fda-lists-22-potential-adverse-effects-of-new-covid-19-vaccine-and-its-not-looking-good/

They also heard that some post-covid patients were "cured" by ivermectin.
https://www.healthrising.org/forums/threads/ivermectin-for-fibro.6491/
https://www.researchgate.net/publication/344318845_POST-ACUTE_OR_PROLONGED_COVID-19_IVERMECTIN_TREATMENT_FOR_PATIENTS_WITH_PERSISTENT_SYMPTOMS_OR_POST-ACUTE

Ivermectin is also under trial for pain management and it also seems to have a connection to the endocannabinoid system. THC's analgesic effects are also mediated through GlyRs, particularly GlyR(alpha)3, where ivermectin can bind. Although ivermectin is also an allosteric modulator of other receptors, such as glutamate-gated chloride channels (GluCls), gamma-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal (alpha)7-nicotinic receptors (alpha7 nAChRs).
https://www.sciencedirect.com/science/article/pii/S0969212617301089

Another thing that can cause flu-like symptoms is nicotine vaccine.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=cannabinoid+antagonist+flue-like&btnG=
(At the first link click on the pdf on the right so you can read the full version.)

A very new research on COVID-19 might just explain our brain fog. COVID-19 infection forces astrocytes to produce some unknown compounds (unidentified neurotoxic factors) that poison their surroundings and kill other neurons.
https://www.medrxiv.org/content/10.1101/2020.10.09.20207464v3.full

Astrocytes can also produce anandamide and other acylethanolamides, so in a few weeks it might turn out if I was actually right or if it is some other compound, but at least we will know!
https://www.sciencedirect.com/science/article/pii/S0021925820849412

Testosterone acts as a double-edged sword in COVID-19 infection.
A low level decreases ACE2 expression (lung protective), while a high level makes one prone to thrombosis.
https://www.sciencedirect.com/science/article/abs/pii/S0306987720321915

My proposal of the use of a cannabinoid antagonist may seem controversial as they can cause flu-like symptoms. However serotonin deprivation syndrome is also said to do so and it still obliterated my flu-like symptoms even if I had some other symptoms. I am also rather perplexed by serotonin as taking the tryptophan supplement also seems to enhance the burning pain, but it generally has a good effect on my general state. As serotonin has a lot of functions in the body it is easily possible that some processes run contrary to each other and while it may ameliorate some symptoms it could also exacerbate others. I still haven't really looked into this part, but I will do so when I get to.

I haven't really checked into this Lyme disease thing, but it really seems like it can cause flu-like symptoms. Even I had one or two tick bites when I was young, still there are those here who had tested negative for lyme, so it really seems like the flu-like state is more likely the body's response to it.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198509


(TLR)3 activation results in the induction of type 1 interferon (IFN-alpha and IFN-beta) and NF(kappa)B-inducible (e.g. IL-1beta, IL-6 and TNF-alpha) inflammatory cascades which are responsible for coordinating the innate immune response to viral infection. Recent data has highlighted that FAAH inhibition attenuates the TLR3-mediated increase in the expression of IFN-inducible genes and pro-inflammatory cytokines in brain regions such as the hippocampus and hypothalamus, without altering peripheral immune responses. The behavioural and physiological consequences of TLR3 activation include the induction of sickness behaviours such as fever/hypothermia, hypoactivity, anorexia and enhanced pain sensitivity, which represents a highly adaptive coping mechanism by the CNS to fight viral infection. However, aberrant activation of TLR3 can elicit adverse effects on the CNS including increased neuronal excitability and seizure susceptibility, impaired contextual and working memory, anxiety- and depressive-like behaviour and exacerbation of underlying neurodegenerative processes. However, it is unknown if FAAH-induced modulation of TLR3-mediated inflammatory responses result in associated physiological and behavioural changes.

This might make it seem so that my theory is wrong and things have to be reversed to work out, but I think an other explanation could be that I have such a crazy amount of AEA production that FAAH is also running at full capacity all the time and this would still result in TLR3 activation and the resultant sickness behavior. We shouldn't also forget that high AEA levels were measured in both PTSD and fibromyalgia, which is rather indicative.
https://www.sciencedirect.com/science/article/abs/pii/S016643281830250X


So now it seems I have some kind of anti-diabetes too as taurine seems to cause a massive neuronal hyperexcitability with pain and apparent hyperalgesia (severe flatulence) just contrary to what is stated in this article.
https://journals.physiology.org/doi/full/10.1152/ajpendo.00168.2004
By the way I had another failed attempt with taurine. I was feeling relatively well in the chronic phase of POIS and haven't eaten anything for a few hours either. So I drank water with 2g taurine and only half an hour later (about 30-60 min) I begin to have a severe burning flatulence. I also began to have a weak heart-ache around 90 minutes, but it wasn't so severe as last time and it is probably because I hadn't eaten anything either with it. Last time I was also in the acute phase, but I simply can't imagine that I could extinguish a fire by dropping coal onto it. It also didn't work with foods, so why would taurine be different. Maybe I will give it a last chance timed to O, but only to see if it does anything else and to confirm that it has an enhancing effect on my POIS. Could it also be that I have some kind of taurine intolerance similar to lactose intolerance or celiac disease?
I had also taken arginine a few times and even 2 g didn't result in any adverse events, although I hadn't noticed any beneficial ones either. Others claimed it takes some time for it to work so I will keep taking it and see what happens.

Some further information on NAC:
A library composed of 958 FDA-approved drugs was screened and five drugs, N-acetylcysteine (NAC), tiopronin (TPR), verteporfin (VP), calcitriol and racecadotril, were identified to inhibit RBD/ACE2 interaction at both low and high concentrations selected.
Calcitriol, an active form of vitamin D3, mildly inhibited RBD/ACE2 interaction.
Racecadotril, an enkephalinase inhibitor and used for treating acute diarrhea, also showed mild inhibition of RBD/ACE2 interaction.
NAC inhibits the binding of RBD to ACE2 through its interaction with RBD, but not ACE2 receptor.
In addition to acting as the receptor of SARS-CoV2, ACE2 possesses additional functions, including lowering blood pressure. Accordingly, targeting the RBD ligand but not the ACE2 receptor is considered another advantage of NAC.
https://link.springer.com/article/10.1007/s13238-020-00803-w


"Vincent M"'s supplementation trial seems to be a good starting point for me as I see some parallelism.
https://poiscenter.com/forums/index.php?topic=81.msg3513#msg3513
I think Ginko biloba also had a mild positive effect, but I just forgot about it.
I haven't really noticed anything with saw palmetto at the time, but it might be that I was not attentive.
I had best try it out separately and in combination with alpha lipoic acid as it also reduced the burning feeling at urination.
The only thing that I don't really get is that he claims that cannabis reduced his symptoms. This doesn't go well with my theory, but it might be some kind of competitive antagonism. I won't try it anyway, because I have never smoked even a normal cigarette and I won't start it now, especially in consideration of my chest pain problems, but CBD oil might still make a difference even if I thought it won't.

I have also just found out that both CBD and Kaempferol inhibits FAAH, so they can theoretically increase AEA. Kaempferol can be found in high concentration in some plants (e.g. saffron, ginger).
So I might just have to reverse my whole theory as ginger seems to work. If cannabinoid antagonists can induce a flu-like state than what is the capsaicin-like compound that I feel burning my body. Maybe trying them (CBD and saffron) will shed some light on the matter.
https://medium.com/@mary_c_biles/anandamide-the-bodys-own-antidepressant-and-how-to-boost-it-naturally-895cdafcf7fe
https://en.wikipedia.org/wiki/Kaempferol
Also I have just realized that I haven't even checked out what capsiate is. It turns out it is a capsaicin analog without its pungency and it can be found even in sweet peppers. However capsiate can still act on similar receptors as capsaicin. This may just be the reason I have problems with sweet pepper too.
https://pubchem.ncbi.nlm.nih.gov/compound/Capsiate

[berlin1984]

Thread continues in https://poiscenter.com/forums/index.php?topic=3733