General Category > POIS Research

FAAH Inhibitors

(1/11) > >>

Progecitor:
Warning! This theory has been mostly disproved experimentally. Bore yourself at your own risk. Saffron and maca are effective though, so be sure to try them! Besides CBD oil is really beneficial for some and FAAH inhibition could be the key to that.

This is a direct continuation of my capsaicin-like thread, but it looks like I may have somewhat erred about anandamide, so I thought it wiser to start a new and clear thread. I also wanted to raise awareness that FAAH inhibitors are probably the best treatment for at least one POIS subtype.

SAFFRON FOR SUFFERING!
It seems I may have to reevaluate my theory regarding the AEA poisoning. I bought some dried saffron and made tea from it. As I expected it to make my symptoms worse I thought it a safer option than CBD oil for a first trial. So as it turns out it doesn't enhance POIS, but actually makes me quite well, not if that was bad thing of course. :)
Unfortunately it cannot itself completely overcome POIS as the local burning still occurs, although to a  lesser degree, but at least it can prevent POIS from becoming a systemic event. Its potency is the best so far (~90% symptom reduction) and seems even greater than that of MACA and its effect is similarly at its peak after 1-3 hours of consumption, which probably indicates that they prevent the capsaicin-like compound from reaching a high concentration in the blood.
After ejaculation there is no tiredness, the eyes remain almost totally clear and there is no blurred vision. I don't have a pronounced brain-fog by the next day, but a slight blunt in focusing capability can still be felt. I also didn't notice the hypothermia effect. Muscle fatigue can still be felt and some rhinitis still occurs however, but to a smaller degree.
Side effects: Some (non-burning) flatulence occurs, which is similar to what I experienced with the other FAAH inhibitors. I have also experienced some sporadic and transient (1-2 second) stabbing pain at different places in the leg, but this is nothing serious.
It remains to be seen what happens in the long run and I will have to tinker with timings and combinations too. I can't buy CBD oil right now, but I will definitely try it when I can.

So it looks like the capsaicin-like compound is not AEA, but rather arachidonic acid and ethanolamine or another metabolite of these. If this holds true than the most likely root of POIS in my case is evidently a malfunction in the endocannabinoid signaling (e.g. FAAH over-activity or high substrate concentration (AEA or 2-AG)) related to the acrosomal reaction. So if there really is an arachidonic acid cascade than the entry point is probably not PLA2, but the conversion of anandamid to AA.
Even if I had false conclusions the information about AEA still seems very important in order to understand the exact mechanism that leads to POIS and to have a chance of cure and not only a treatment, however good it may be.

As AA involvement has been indicated in other threads on the site a broader view can be gained in combination with my theory. From my point of view the most important question is if AA is able to activate the TRPV1 channel as it is the deciding factor if it can be the capsaicin-like compound which I seek. The answer seems to be a yes, as AA and some of its lipoxygenase products  (12-(S)-HPETE, 15-(S)-HPETE, 5-(S)-HETE and leukotriene B4) are able to activate TRPV1 at fairly high concentrations. Conversely it also means that their concentrations are probably very high.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/bjp.2008.216

Actually I have found a recently published book that goes into detail about FAAH inhibitors. It turns out that MACA also contains FAAH inhibitors (macamides). Besides this other inhibitors can be found in nutmeg, flavones, isoflavones (soy bean, chickpeas), and some algae. Steroids also affect FAAH activity of which pregnenolone has the greatest efficacy, testosterone and cortisone were effective in higher concentrations, while hydrocortisone, estradiol and pregnenolone were better at low molar ratios.
A year ago my mother made some falafel and I remember that I felt better from it. I wanted to eat it again, but I just forgot about it. As the main ingredient of falafel is chickpeas it was probably not accidental.
I haven't eaten nutmeg since I was a child, but around the time I began to masturbate I remember that we used it frequently for spicing. Could this have been the initiator of my POIS!?
https://books.google.hu/books?id=5S8KEAAAQBAJ&pg=PA373&dq=macamides+FAAH&hl=hu&sa=X&ved=2ahUKEwjbsNjbwYjvAhXIShUIHW75AcQQ6AEwAXoECAAQAg#v=onepage&q=macamides%20FAAH&f=false

Progesterone Up-Regulates Anandamide Hydrolase in Human Lymphocytes.
Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human lymphocytes.
Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level, and was partly mediated by the Th2 cytokines. In fact, lymphocyte treatment with IL-4 or with IL-10 had a stimulating effect on FAAH, whereas the Th1 cytokines IL-12 and IFN-? reduced the activity and the protein expression of FAAH. Human chorionic gonadotropin or cortisol had no effect on FAAH activity.
https://www.jimmunol.org/content/166/12/7183.short

The only thing the authors forgot to mention that this article is actually about POIS! :)
Melatonin has appeared to stimulate IL-2 and IL-12 secretion and to inhibit the release of most inflammatory cytokines, namely TNF-alpha.
According to the data available up to now, it seems that melatonin may preferentially act on the lymphocyte system by stimulating IL-2 release from TH1 cells, which have been proven to express melatonin receptors, while 5-methoxytryptamine would mainly modulate the macrophage system by piloting its function in an antitumor way.
However, it has been demonstrated that the pineal gland, in addition to direct immunomodulating action through the release of its indole hormones, may also influence the immune functions by a regulation of the two major brain interneural immunoregulatory systems, consisting of brain cannabinoid and opioid systems.
The functional status of the endogenous cannabinoid system may be simply evaluated by determining the blood levels of the main enzyme involved in the metabolic degradation of cannabinoids, the so-called fatty acid amide hydrolase (FAAH). Then, the evidence of abnormally high blood concentrations of FAAH would reflect a condition of hypofunction of the endogenous cannabinoid system.
This might be so in my case!
Then, the biological response occurring during the inflammatory systemic diseases could be modulated and controlled by acting on the cannabinoid system through the administration of cannabinoid agonists, which may be considered as novel anti-inflammatory agents.
Cannabinoids may influence several cytokine secretions, but their main effect would consist of the inhibition of IL-17 secretion. Then, since the enhanced IL-17 secretion would constitute the main autoimmunity-related cytokine alteration, the inhibitory effect of cannabinoids on IL-17 secretion justifies their use in the potential treatment of all autoimmune pathologies. The pineal gland may modulate the cannabinoid system in an immunostimulatory way, then the pineal-brain cannabinoid system would constitute a fundamental functional axis responsible for the generation of an appropriate immune response. The main endogenous cannabinoid agents are arachidonoyl-ethanolamide (AEA), also called anandamide, and 2-arachidonyl-glycerol (2-AG), and they are both characterized by a circadian rhythm in their secretion, with higher levels of AEA during the night and higher levels of 2-AG during the day. On the contrary, brain opioid interneuron system would play a major immunosuppressive activity, particularly by acting on mu-opioid receptor.
From this point of view, it is interesting to observe that beta adrenergic agonists may allow apoptosis of all lymphocyte subsets, whereas the only T reg lymphocytes may be paradoxically stimulated in their functions. On the same way, all lymphocyte subsets are inhibited by the mu-opioid agonists, whereas T reg cells would be stimulated since the administration of the mu-opioid antagonist naloxone has been proven to inhibit T reg cell activity. The cytokine network and the neuroendocrine system are connected by several links, and one of the main cytokines involved in realizing a connection between the cytokine network and the neuroendocrine system is IL-12 itself, which has appeared to inhibit FAAH activity, with a consequent increase in brain endogenous cannabinoid content.
So melatonin is also a FAAH inhibitor! This could be the link to tryptophan and serotonin deprivation syndrome.
https://asclepiusopen.com/clinical-research-in-hematology/volume-3-issue-2/1.pdf

Different natural compounds are natural inhibitors of FAAH in vitro. They include some flavonoids such as kaempferol, apigenin, luteolin, quercetin, myricetin and genistein.
http://www.fedoa.unina.it/12652/1/DeLuca_Lucia_31.pdf#page=126

A combination of kaempferol and apigenin seems especially promising based on their potency.
Apigenin ca be found in parsley, celery and teas. Besides FAAH apigenin also inhibits PDE 1–3, PI3-kinasea, COX-2, PPARg. Kaempferol can be found in broccoli and endives (chicory).
Now this is rather strange as I haven't experienced anything definite with Sulforphane (broccoli extract), although I only tried it a few times, but I remember that eating broccoli cream soup made me feel better.
Other effects of kaempferol are activation of PPARg and inhibition of interleukin-4-induced STAT6 activation.
The finding that both apigenin and kaempferol activate PPARg is worthy of comment. PPARg is a ligand-activated transcription factor that, in addition to its role in adipocyte differentiation, fatty acid and lipid metabolism, and insulin sensitivity, also has potentially important roles in inflammation and cancer. There appears to be an overlap between this system and the endogenous cannabinoid (endocannabinoid) system (itself important in inflammation and cancer), as the endocannabinoid ligands anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol interact with PPARg. This overlap also includes the phytoestrogen genistein, the isoflavone analogue of apigenin, which activates PPARg at micromolar concentrations and is a potent competitive inhibitor of FAAH (Ki value 2.8 um). The related isoflavone compound daidzein (the isoflavone analogue of 4',7'-dihydroxyflavone, a flavonoid found in alfalfa roots (available as a supplement, but I haven't tried it yet) also inhibits rat brain FAAH in a competitive manner, with a Ki value of 1.7??m and activates PPAR?.
Tobacco leaves contain kaempferol glycoside, raising the possibility that a local inhibition of FAAH in the lungs occurs after cigarette consumption. Given that AEA, which is often produced at high levels following cellular damage, induces cough, a high local concentration of kaempferol would hardly be beneficial to smokers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538700/

Kaempferol, known chemically as 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one, can be isolated from black, green, and mate herb teas, as well as from numerous common vegetables and fruits, including beans, cabbage, grapes, broccoli, strawberries, kale, gooseberries, citrus fruits, Brussels sprouts, grapefruit, apples, dry raspberry, and tomatoes, and from plants or botanical products commonly used in traditional medicine such as mums (chrysanthemum spp.), ginkgo biloba (Ginkgo biloba L), lime trees (Tilia spp.), Chinese milkvetch (Astragalus mongholicus), field horsetail (Equisetum spp.), moringa (Moringa oleifera), and the Japanese pagoda tree (Sophora japonica).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838523/
This is interesting as I find things that make me both better or ill. As plants contain many chemicals which can be both good and bad, it seems logical that the net effect should be considered.

Unfortunately there are no FAAH inhibitor medications currently on the market, even though they were in development a few years ago, but then a major incident happened and then the clinical trials for every other prospective agents were suspended. Maybe understanding the function of FAAH in connection with POIS could lead to safer drug development and it could be especially important if it is also involved in COVID-19 infection.
https://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase#Inhibitors

Neobavaisoflavone can be found in high concentration in Psoralea corylifolia Linn. (also known as Babchi seeds, Bakuchi powder, Bakuchiol, malay tea) and it is an efficient natural inhibitor of FAAH.
https://pubs.acs.org/doi/abs/10.1021/acs.analchem.9b05826
https://pubs.acs.org/doi/suppl/10.1021/acs.analchem.9b05826/suppl_file/ac9b05826_si_001.pdf

Care should be taken with Psoralea corylifolia seeds as it can cause acute hepatitis. This is especially true for those like me, who also have Gilbert disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127755/

Psoralea corylifolia has many beneficial health effects, but some rather worrying adverse effects too.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249905/

Neobavaisoflavone is also a potential anti-COVID-19 drug agent.
https://www.sciencedirect.com/science/article/pii/S0006291X20321264?via%3Dihub

Saffron (crocetin) effectively binds to the spike protein and also the main protease of COVID-19, although based on my findings it may even ameliorate the metabolic changes caused by the virus. So it could be the ultimate anti-covid-19 wonder drug and it possibly helps post-covid patients too.
https://www.sciencedirect.com/science/article/pii/S240584402032524X

If someone has trouble with sleeping after O, then it is possible that FAAH hydrolyzes oleamide, which is an endogenous sleep-inducing factor. Actually I can't sleep more than 6-7 hours since taking saffron, but at least I wake up much fresher without the usual brain fog.
https://www.sciencedirect.com/science/article/abs/pii/S0090698002000539

I have also tried another supplement that works and it is Cordyceps [500 mg per capsule]. It has a lesser effect than the other medicinal mushroom I used, but taking about three capsules per day has a noticeable positive effect.
I suspected a FAAH inhibitory activity, but instead I found that Cordyceps is a COX-2 and iNOS inhibitor.
Cordyceps protects from oxidative stress caused by reactive oxygen species (ROS).
The results indicate that treatment with the CM extract down-regulates COX-2 and iNOS protein expression in H2O2-induced C6 glial cells, whereas H2O2 up-regulates COX-2 and iNOS expression.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Anti-inflammatory+effects+of+Cordyceps+militaris+extracts&btnG=

I was also experimenting (once) with Cistus incanus tea which is supposed to be effective in covid.
Well I got a heart ache reminiscent of my experiences with fish oil (DHA/EPA) and Aspirin (also COX inhibitor). I am not exactly sure about it, but I suspect myocarditis as the underlying issue. Actually having an O can accelerate the disappearance of the symptom, although I haven't tested this with everything. Unfortunately I am not sure about the other effects of Cistus as I was quite well at the time anyway, so I only experienced its adverse effect.
Later I realized that Cistus incanus actually has a proven COX inhibitory property.
A don't remember if I had any heart ache from apigenin even though it is also a COX-2 inhibitor, but who knows.
https://www.tandfonline.com/doi/abs/10.1080/14786419.2015.1089242
This is a really unpleasant symptom, so I don't like experimenting with it, but later I might consider so.
Maybe I should test naproxen (another COX inhibitor) and see if it does something similar.

Both AEA and AA induces platelet aggregation.
Aspirin is known to inactivate cyclooxygenase irreversibly in various cell types. This leads to the complete inhibition of AA-induced platelet activation.
So is the reason why I get a heart ache from Aspirin due to platelet aggregation inhibition? Blood tests don't indicate that I would have any problem with blood coagulation even in acute state. Or this is just yet another thing that seems to work in a reverse way in my body.
https://febs.onlinelibrary.wiley.com/doi/full/10.1016/S0014-5793%2800%2901359-4

Taurine depletion can cause cardiomyopathy.
As taurine supplementation in a great dosage definitely enhances POIS and can cause a heart ache it could indicate a connection (e.g. taurine overload?).
https://link.springer.com/article/10.1007%2Fs00726-015-2110-2

Anandamide can be metabolized by cyclooxygenase-2 (COX-2) to produce prostaglandin E2 (PGE2) ethanolamide.
https://www.sciencedirect.com/science/article/pii/S002192581965739X

Ibuprofen is also a FAAH inhibitor.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=ibuprofen+FAAH&btnG=

Cholesterol increases the substrate accessibility of FAAH.
This probably has something to do with vitamin D supplementation.
https://portlandpress.com/biochemj/article-abstract/457/3/463/46408

Women POISers should consider trialing vaginal suppositories that contain boric or boronic acid as it also has a FAAH inhibitory property and it may help after sexual activity. Boronic acid is used as a conservating agent. I will try this later to see if it does anything if taken orally. Unfortunately it keeps accumulating in the body leading to intoxication, so it can't be used on the long run.

I tried one of the vitamin-B supplements called D-Biotin (also called vitamin B7) [300 ug per capsule]. I mentioned earlier that I had bad experiences with vitamin-B complex and biotin is not an exception as it makes me very ill even when I took it in the chronic phase.
More than 10 years ago I also had bad experience with magnesium + vitamin B6 and at the time I thought it was magnesium, but a few years ago I also tried a vitamin-B complex and that is when I realized that it has to be vitamin-B that causes POIS enhancement. I want to test all vitamin-B, but unfortunately I still couldn't get my hands on niacin, which could be the most interesting.

Interestingly eating a lot of egg whites could induce biotin deficiency in a few weeks.
Unless I have a high level already how else could it induce toxicity?
Signs of frank biotin deficiency may be observed in individuals with deficiencies in biotin, HLCS, and biotinidase and in individuals consuming large amounts of raw egg white; the biotin-binding protein avidin in raw egg white causes a substantial decrease in the bioavailability of biotin.
Based on the observation that HLCS and biotinidase deficiency patients are treated with pharmacological doses of biotin for their entire life with no apparent signs of toxicity, one can assume with reasonable confidence that the toxicity of biotin is very low.
https://academic.oup.com/advances/article/3/2/213/4644561?login=true

Arachidonic acid and prostaglandin deficiency is considered highly teratogenic in pregnancy just like biotin deficiency is. Cyclooxygenase inhibitors (e.g., indomethacin, aspirin, phenylbutazone) also inhibit the protective effect of arachidonic acid in this regard.
https://academic.oup.com/jn/article/139/1/154/4750877?login=true

Just a few weeks ago my mother baked a cake stuffed with walnuts and I ate a whole lot of it even though I knew I was going to feel much worse. Needless to say it was burning like hell and multiple MACA capsules had a hard time pulling it down. So do walnuts contain any capsaicin? Of course they don't. What they actually contain are precursors of arachidonic acid.
Walnuts are also richer than most other nuts in polyunsaturated fats. The most abundant one is an omega-6 fatty acid called linoleic acid. They also contain a relatively high percentage of the healthy omega-3 fat alpha-linolenic acid (ALA). This makes up around 8–14% of the total fat content. (google)
Although some things still doesn’t seem right, so there is no easy solution. I consumed some chia and flax seed in the past in smaller amounts, but I didn't notice any effect. It is true that I wasn't even aware that it could have an effect, so I will try to combine the two in somewhat greater amounts and see if anything happens.
https://en.wikipedia.org/wiki/Alpha-Linolenic_acid
I have noticed some adverse events related to omega-6 fatty acids, however others don't seem to have any ill effects, which is rather contradictory. Actually arachidonic acid seems to be present in great amounts in meat of which I don't really have any problems. Maybe these effects only appear after prolonged consumption, but then again it doesn't seem to be the case with walnuts.
https://en.wikipedia.org/wiki/Omega-6_fatty_acid
Maybe I specifically have a problem with gamma-Linolenic acid (GLA) as I think I remember something about rapeseed oil too, but it was such a long time ago, that I have to recheck that too.
https://en.wikipedia.org/wiki/Gamma-Linolenic_acid

Arachidonic acid induces a rapid cAMP production. Both this effect and its long-term adipogenic effect are impaired by cyclooxygenase inhibitors such as aspirin and indomethacin.
https://www.sciencedirect.com/science/article/pii/S0022227520312141

Phospholipases A2 (PLA2s) are enzymes that cleave fatty acid in position two of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycerol molecule. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond, releasing arachidonic acid and lysophosphatidic acid. Upon downstream modification by cyclooxygenases or lipoxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes, which are categorized as anti-inflammatory and inflammatory mediators.
PLA2 enzymes are commonly found in mammalian tissues as well as arachnid, insect, and snake venom. Venom from both snakes and insects is largely composed of melittin, which is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite, arachidonic acid is released from the phospholipid membrane disproportionately. As a result, inflammation and pain occur at the site. There are also prokaryotic A2 phospholipases.
https://en.wikipedia.org/wiki/Phospholipase_A2
As it seems like I get bitten in the ass by snakes or spiders every time I ejaculate I don't think I can get any more desensitizated to it. :D

A possible explanation for itching skin in relation to this.
In Langerhans cells, niacin can activate GPR109A to increase intracellular Ca2+. This Ca2+ increase triggers phospholipases, predominantly Phospholipase A2 (PLA2), to release arachidonic acid from cellular lipid stores. Free arachidonic acid serves as a precursor to the production of eicosanoids, including lipoxygenases, thromboxanes and prostaglandins.
The production of PGI2 and PGD2 decreases after repetitive administration of niacin in parallel with the development of flushing tolerance.
Another potential target would be to inhibit the ability of PLA2 to produce arachidonic acid, thereby eliminating the production of prostaglandins upstream of COX. Glucocorticoids can indirectly inhibit PLA2, but there are currently no approved therapies that specifically target this enzyme.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-1241.2009.02099.x

https://poiscenter.com/forums/index.php?topic=3551.msg38066#msg38066
ctrl+f: bee venom
Plaquenil antagonizes PLA2, which leads to lesser arachidonic acid production. The active agent of Plaquenil is Hydroxychloroquine, which is of course used in COVID-19 treatment. So my problem is apparently with FAAH, but it could be still interesting to see if Hydroxychloroquine also worked.
It may be of note that honey bee venom can be both beneficial and harmful in CFS patients, which in my opinion implies a bipolarity in disease manifestation for both CFS and POIS.
https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Treatments/Hydroxychloroquine-Plaquenil

It is a rather important fact that AEA can accumulate inside cells, although the exact mechanism is still not known. Even if a by-product (AA) is the cause it can still explain the rapid release of the compound, as I don't have a burning sensation either at the prostate or the testes before O. This could also explain the confusion with the allergic hypothesis.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0705468

We next examined the effects of genetic or pharmacological blockade of FAAH on NAE accumulation in mouse tissues. Anandamide (C20:4 NAE) was highly elevated (>8-fold) in brain, liver, and testis of FAAH(-/-) or PF-3845-treated mice, and was modestly elevated in some but not all of the other tissues analyzed. Curiously, the accumulation of anandamide following FAAH disruption was not correlated with the basal concentrations of this lipid or the FAAH enzyme itself. For instance, FAAH disruption caused dramatic elevations in anandamide in testis, but not kidney, despite both tissues possessing high basal anandamide concentrations and FAAH activity.
We also measured additional NAEs, including the polyunsaturated species C18:2 and C22:6 NAE, which share physicochemical properties with anandamide, and several saturated or monounsaturated NAEs (C16:0, C18:0, C18:1, and C22:0). Brain was the only organ that showed large increases (>5-fold) in all NAE species following FAAH blockade, although the C22:0 NAE was selectively elevated in FAAH(-/-) mice but not mice treated with PF-3845. In contrast, testis tissue from FAAH-disrupted animals accumulated high amounts of anandamide and C22:6 NAE, but displayed only modest changes in other NAEs. Livers from these animals selectively accumulated anandamide and C18:2 NAE, but not C22:6 NAE, and, like testis, showed more-limited accumulation of saturated and monounsaturated NAEs.
Both brain and testis appear to possess an enzymatic route to rapidly generate polyunsaturated NAEs, including anandamide. That testis can furthermore accumulate anandamide without substantial elevations in shorter chain NAEs suggests that at least two additional NAPE-PLD-independent NAE biosynthetic pathways may exist, one for polyunsaturated NAEs and the other for shorter chain saturated and mono-unsaturated NAEs.
https://www.jlr.org/article/S0022-2275(20)40529-2/fulltext

Overall, these findings suggest that adiposomes may have a critical role in accumulating AEA, and possibly in connecting plasma membrane to internal organelles along the metabolic route of this eCB. In line with these data, depletion of a pre-existing pool of 2-arachidonoylglycerol has been recently shown as a key event in sperm activation, speaking against the on demand synthesis of this eCB much alike that of AEA.
https://www.frontiersin.org/articles/10.3389/fnmol.2017.00166/full

It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.
https://link.springer.com/article/10.1007/s11011-018-0195-5

CBG is an inhibitor for the uptake of the endocannabinoid ligand anandamide.
https://www.mdpi.com/2079-6382/9/6/297/htm

Cannabinoids can suppress inflammation and cytokine storm in ARDS in relation to COVID-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677512/

Anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.
https://jpet.aspetjournals.org/content/321/1/370.short

Recently, we have demonstrated that testosterone regulates mu-opioid receptor and cannabinoid 1 receptor (CB1) expression via transcriptional activities of androgen receptor in a trigeminal pain model.
https://www.sciencedirect.com/science/article/pii/S0166432818302870

Though opioids and cannabinoids can independently cause analgesia and respiratory depression (RD) that could be reversed by respective antagonists in monkeys and FAAH inhibition can attenuate morphine withdrawal effects in mice.
https://www.nature.com/articles/tpj201479

FAAH can hydrolyze other endocannabinoids, including 2-AG.
FAAH has a major role in regulating the magnitude and duration of anandamide signaling.
Western blotting analysis showed that FAAH, CNR1, and CNR2 are present in the testis and epididymis of WT mice.
In contrast, CNR2 was localized in spermatocytes and Sertoli cells encircling spermatocytes and spermatids in the testis. In the epididymis, epithelial cell surfaces demonstrated CNR2 immunostaining, whereas signals were undetectable in interstitial cells. FAAH was present in spermatocytes and spermatids, while spermatogonia had little or no positive signal. Sertoli cells and Leydig cells also showed positive staining of FAAH. The localization of FAAH was evident on cell surfaces of the epididymal epithelium.
The presence of FAAH on the testis and epididymis suggests that endocannabinoid levels are tightly regulated by FAAH in these tissues.
Our findings of the presence of FAAH, CNR1, and CNR2 in the testis and epididymis and the presence of FAAH and CNR1 in sperm suggest that endocannabinoid signaling has a role in spermatogenesis and sperm maturation.
Sertoli cells exposed to higher anandamide levels were shown to undergo apoptosis, and FAAH activity is regulated by FSH in mouse Sertoli cells. In addition, sperm fertility and the acrosome reaction were reported to be adversely affected if exposed in vitro to high anandamide levels.
This information is of course not necessarily accurate in humans.
https://academic.oup.com/biolreprod/article/80/2/235/2557552?login=true

We conclude that the serine hydrolase ABHD2 is the nongenomic progesterone (P4) receptor of sperm.
Metabolic serine hydrolases acting as monoacylglycerol lipases convert AGs into glycerol and AA. By hydrolyzing AGs in a P4-dependent manner, ABHD2 releases calcium channel (CatSper) from AG inhibition, which liberates AA. During sperm transit through the epididymis, the plasma membrane undergoes lipid remodeling, which results in reduced levels of AA and altered sperm motility, perhaps by means of modification of the ion channels’ function. Indeed, we found that application of AA briefly activates CatSper, whereas prolonged incubation in 3 uM AA results in CatSper inactivation and loss of P4 sensitivity. In accordance with our model, an overabundance of AA should negatively regulate ABHD2 activity; therefore, continuous P4 application will result in a considerable accumulation of AA in the outer leaflet of the sperm plasma membrane, which would ultimately lead to CatSper desensitization. However, prolonged P4 exposure does not cause CatSper desensitization. It is possible then, that during exposure to P4, liberated AA diffuses into the inner membrane leaflet or is released into the extracellular medium. Indeed, under our experimental conditions, any compound released from the plasma membrane will be removed by continuous perfusion. It is possible that AA removal from the outer leaflet in vivo could be achieved by either fatty acid transporters or chelation by albumin, which is abundant in the female reproductive tract.

Both murine and human CatSper are up-regulated by intracellular alkalinization; however, P4 exposure is also required for full human CatSper activation. This is explained by the fact that ejaculated human spermatozoa retain a substantial amount of 2AG; therefore, P4 activation of ABHD2 is needed for 2AG clearance. That MAFP-treated cells still respond to PGE1 points to an intriguing possibility that PGE1 may stimulate CatSper by allosteric activation of CatSper or may compete with 2AG directly for the binding site. Prostaglandins are derivatives of AA and are structurally similar to the 2AG tail; however, such a hypothesis requires additional experimental confirmation.

It is possible that the P4-ABHD2-endocannabinoid axis could also regulate female reproduction by a similar mechanism. In fact, the expression of endocannabinoid system components was previously linked with genomic steroid activity.

In addition, our model suggests that AGs are continuously produced to block CatSper, unless progesterone stimulates their hydrolysis by ABHD2 contradicting the "on-demand synthesis model" of endocannabinoid activity, whereby these lipids act only upon stimulus-dependent release from their precursors.
https://science.sciencemag.org/content/352/6285/555

In a high concentration even AEA can be toxic.
Inhibition of CB1, CB2, VR1 or NMDA receptors by selective antagonists did not reduce AEA neurotoxicity. Anandamide-induced neuronal cell loss was associated with increased intracellular Ca2+, nuclear condensation and fragmentation, decreases in mitochondrial membrane potential, translocation of cytochrome c, and upregulation of caspase-3-like activity.
https://www.nature.com/articles/4401442

We hypothesize that AEA may induce either neuroprotection or neurotoxicity, depending on the balance of its action on CB1 receptors on the one hand, and VR1 receptors or calcium-mediated signal transduction pathways on the other.
https://journals.sagepub.com/doi/full/10.1097/00004647-200405000-00011

I have also stumbled upon an interesting article about reductive stress. Researchers say that contrary to popular ideology not only oxidative stress, but even reductive stress can lead to reactive oxygen species (ROS) generation. Excessive amounts of antioxidants can lead to so called reductive stress or anti-oxidative stress (RS/AS). Surplus antioxidants are pathogenic for hearts and skeletal muscle. Reductive stress can be induced by hypoxia. I think that reductive stress might be involved in some cases of POIS. In my case I suspect oxidative stress, but I still don't get the whole picture, especially as there are conflicting data. Nevertheless I highlighted some information that seems interesting in this regard. I also suspect this has to do something with the connection between POIS and viral infections. Oxidative stress in theory could rebalance the redox system in the case of an ongoing reductive state. Viral infections usually cause oxidative stress, but in some cases they may also induce reductive stress (e.g. COVID-19) just to make things even more complicated.
https://medicalxpress.com/news/2020-05-surplus-antioxidants-pathogenic-hearts-skeletal.html
Actually they used sulforaphane for their tests, which is also an antioxidant. I used NAC and sulforaphane together in combination for a few days. I haven't really noticed much change. Maybe my eyes were a bit clearer, but otherwise nothing substantial happened. Later I will test them in greater dosage or pair them with a glutathione (GSH) supplement when I can afford it.

A reduction in serum level of superoxide dismutase (SOD3) was observed in allergic rhinitis (AR) patients. SOD3 overexpression inhibited the release of proinflammatory cytokines including tumor necrosis factor-a, interleukin (IL)-4, and IL-6. Its overexpression also ameliorated the loss of interferon-g. An OVA-induced AR animal model study showed that taurine was efficacious in alleviating allergic inflammatory reactions by relieving behavior symptoms of AR mice and reducing eosinophilic and mast cell infiltration into the nasal cavity. In addition, taurine treatment increased the production of SOD3 and PPAR-g, which, in turn, suppressed expression of proinflammatory cytokines through phosphorylation of ERK1/2. Conclusion: Taurine could potentially serve as a therapeutic treatment for allergic disorders.
https://www.karger.com/Article/Abstract/505209

In addition, reductive stress resulting from high NADH is also associated with elevated ROS production under ambient oxygen tensions. For example, addition of exogenous complex I substrates, such as glutamate plus malate, or a-KG, significantly augmented NADH levels and mitochondrial membrane potential, which stimulated H2O2 production by ~10-fold in isolated rat brain mitochondria.
Treating rat L6 myoblasts with the antioxidant N-acetyl-l-cysteine (NAC; 1 mM for 1 h) induced reductive stress by increasing the NADH/NAD+ ratio, mitochondrial H2O2 levels, and free radical leak.
NADPH and GSH are essential for oxidative stress defense; and NADPH is indispensable for GSH recycling by GR.
However, excessive levels of cellular GSH and/or NADPH also lead to reductive stress.
https://www.liebertpub.com/doi/full/10.1089/ars.2019.7803

Exposure of HT22 cells to H2O2 led to accumulation of intracellular ROS, and simultaneous treatment with AEA markedly reduced the generation of ROS. SOD plays a vital role in protecting cells against oxidative injury. H2O2 treatment sharply decreased SOD activity in HT22 cells, and AEA restored SOD activity. GSH is also an important cellular antioxidant. H2O2 treatment sharply decreased GSH activity in HT22 cells. Simultaneous application of AEA partially restored GSH levels. GSSG levels were increased in response to H2O2 treatment and this effect was almost entirely abolished by AEA, which reduced GSSH levels. The GSH/GSSG ratio was reduced by H2O2 treatment, and AEA partially restored this balance, increasing the ratio. The influences of AEA on intracellular ROS, SOD, GSH, GSSG, and GSH/GSSG ratio were abolished by the CB1 antagonist AM251, indicating that the antioxidative effects of AEA may be mediated via CB1 of HT22 cells.
https://www.hindawi.com/journals/omcl/2014/893516/

Astrocytes play a key role regulating aspects of inflammation in the central nervous system (CNS). Several enzymes, such as the inducible nitric oxide synthase (iNOS) or the cyclooxygenase-2 (COX-2), along with different inflammatory mediators such as the free radical nitric oxide (NO) or proinflammatory cytokines, have been proposed to be involved in the cell damage associated with neuroinflammation. Cannabinoid agonists decrease neurotoxicity and release of proinflammatory factors from activated glial cells and anandamide itself is able to promote antiinflammatory responses in astrocytes via CB1 cannabinoid receptors.
https://onlinelibrary.wiley.com/doi/abs/10.1002/glia.20229

Iwillbeatthis:
Can you put the font size in normal size please - you're clogging up the recent posts feed....

berlin1984:
Thank you for bringing up Saffron, it seems it was not mentioned much before in the forum.

I just ordered some extract and will report back. It sounds like a good alternative to SJW (St John's Wort) which decreased my gut motility way too much.

https://nootropicsexpert.com/saffron/
https://selfhacked.com/blog/saffron/

maybe you need a combination of saffron and something else, maybe cetirizine? (i have not read your post in full detail yet..)

FYI, I get this "caipiscin butthole burning" feeling only from masturbation, not from sex :-(
(And in general, POIS is much much worse from masturbation)
(...for people claiming POIS is a rare thing: Why do all religious text ask men to stop masturbating then?!)

Progecitor:
Kaempferol induced apoptosis in glioma cells by elevating intracellular oxidative stress. Heightened oxidative stress was characterized by an increased generation of reactive oxygen species (ROS) accompanied by a decrease in oxidant-scavenging agents such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). Knockdown of SOD-1 and TRX-1 expression by small interfering RNA (siRNA) increased ROS generation and sensitivity of glioma cells to kaempferol-induced apoptosis.
Kaempferol is one of the most important constituents in ginkgo flavonoids.
Ten adult volunteers with an average age 28 years were given a single oral dose of six tablets of Ginkgo biloba extract.The absorption half life was 1.51 hr and elimination half-life was 1.56 hr.
https://pubchem.ncbi.nlm.nih.gov/compound/5280863

Lavender is another FAAH inhibitor.
Investigations into the mechanism of action showed that Lavender essential oil (LEO) markedly decreased the phosphorylation of ERK1, ERK2, and JNK1, and decreased the levels of iNOS in the spinal cord; involvement of the endocannabinoid system was also detected using in vitro inhibition of the FAAH and MALG enzymes as well as in vivo experiments with the CB1 antagonist. Conversely, no effect on P38 phosphorylation and NF-kB activation was detected. These antihyperalgesic effects appeared at the same dose able to induce antidepressant-like, anxiolytic-like, and anorexic effects. LEO was less potent than the inhibitor but was able to inhibit both enzymes, particularly FAAH.
https://www.frontiersin.org/articles/10.3389/fphar.2019.00472/full?fbclid=IwAR0VT30BvI5BqMlYN1o2z8GhPl7V5Idbld6TXsxOnOn42yoAhVdI7o5z3cs
I have just tried it by drinking a liter of lavender tea. It seems to have a weak effect that appears quite slowly about 2-3 hours after consumption. This is a preliminary trial and has to be tested much more of course.

Is the similarity just a coincidence or are the other compounds FAAH inhibitors as well?
We identify ten compounds against the SARS-CoV-2 virus: (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin).
(A) emodin anthrone (Aloe vera), (B) kaempferol (Urtica dioica, Passiflora incarmata, Prunus pérsica L., Tilia mexicana and Tilia europea), (C) quercetin (Passiflora incarmata, Tilia europea, Taraxacum officinale, Matricaria recutita, Prunus pérsica L., Tilia mexicana and Urtica dioica) (D) aesculin (Taraxacum officinale), (E) cichoriin (Taraxacum officinale), (F) luteolin (Scoparia dulce L., Taraxacum offcinale and Passiflora incarmata), (G) matricin (Matricaria recutita), (H) riolozatrione (Jatropha dioica), (I) monocaffeoyl tartaric acid (Taraxacum officinale), (J) aucubin (Verbascum densiflorum).
https://www.mdpi.com/2218-273X/11/2/216/htm

The content of the potentially health-defensive and disease-preventive flavonoids quercetin, kaempferol, myricetin, apigenin and luteolin of 31 vegetables were determined. Quercetin levels in the edible parts of most vegetables were generally below 10 mg/kg, except for onions (67-121.5 mg/kg), lettuce (13.5-35.0 mg/kg), dill (74.5 mg/kg), broccoli (15.5 mg/kg) and spinach (272.2 mg/kg). Kaempferol was below 30 mg/kg except for parsnip (66.4 mg/kg) and leek (45.8 mg/kg). Myricetin could only be detected in lettuce, Swedish turnip, parsley and celery leaves, and dill. Detectable amount of luteolin was in radishes, some representatives of Brassica, sweet peppers, celery leaves and spinach while apigenin was only in Swedish turnip, celery root and celery leaves.
https://akjournals.com/view/journals/066/29/4/article-p345.xml

Check out Table 1. which contains a good list of medicinal plants with high quercetin content.
https://www.researchgate.net/profile/Gabriele-Carullo/publication/326447772_Quercetin_and_its_Natural_Sources_in_Wound_Healing_Management/links/5cf24052299bf1fb184e936a/Quercetin-and-its-Natural-Sources-in-Wound-Healing-Management.pdf

The other common trait for the best working FAAH inhibitors is PPARG modulation.
Looking at innovative targets, a recent paper describes Macamides, a group of secondary metabolites isolated from the plant Lepidium meyenii (Maca). These compounds are benzylamides of fatty acids, active as analogues of the endocannabinoid anandamide (AEA) and studies have demonstrated that they inhibit fatty acid amide hydrolase (FAAH), blocking AEA hydrolysis. Gugnani et al. demonstrated a neuroprotective role of macamides in vitro and in vivo. Macamides reduced Mn-induced mitochondrial toxicity in glioblastoma U-87 MG cells, probably by binding the CB1 receptor, and it could thus be useful in the treatment of neurodegenerative diseases, especially Alzheimer's Disease. Like AEA, macamides can interact with PPARG, regulating inflammation, energetic metabolism and glucose homeostasis, all important factors for the prevention of AD.
https://www.mdpi.com/2304-8158/10/1/29/htm

Saffron is also an agonist of PPARG and interestingly down-regulates IL-12, even tough it still has FAAH inhibitory property. Is PPARG agonism more important than FAAH inhibition?
Furthermore, the beneficial effects of saffron on inhibition of serum levels nuclear transcription factor kB (NF-kB) p65 unit, tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g) and some interleukin (IL) such as IL-1B, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-kB and the agonist of peroxisome proliferator-activated receptor gamma (PPARG). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535192/

Some information on PPARG (google):
PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis. Low PPAR-gamma reduces the capacity of adipose tissue to store fat, resulting in increased storage of fat in nonadipose tissue (lipotoxicity).

Some other agonists of PPAR-gamma:
Arachidonic acid (seriously!?), Berberine, Cannabidiol, Daidzein, Genistein, Ibuprofen, 15-HETE and more.
Well I am rather speechless, but I haven't yet tried CBD or Ibuprofen so I can't really say anything.
PPARG increases insulin sensitivity by enhancing storage of fatty acids in fat cells (reducing lipotoxicity), by enhancing adiponectin release from fat cells, by inducing FGF21 and by enhancing nicotinic acid (niacin) adenine dinucleotide phosphate production through upregulation of the CD38 enzyme.
Muon also found a connection to CD38 and it seems that both quercetin and apigenin are CD38 inhibitors.
https://poiscenter.com/forums/index.php?topic=2545.msg39497#msg39497
https://en.wikipedia.org/wiki/Niacin
https://en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_gamma
(At the bottom of the page click on show PPAR modulators.)
Berberine also has a connection to S-adenosyl methionine (SAM).
The alkaloid berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom as a bridge. Formation of the berberine bridge is rationalized as an oxidative process in which the N-methyl group, supplied by S-adenosyl methionine (SAM), is oxidized to an iminium ion, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.
https://en.wikipedia.org/wiki/Berberine

Progecitor:
I swear that I have just found this!
A theory about COVID-19 infection leading to a systemic FAAH hyper-activation.
Since FAAH hyper-activation may also allow an excessive immune-inflammatory responses, coronavirus infection might induce an excessive inflammatory response by determining an ECS deficiency. In other words, viral spike glycoprotein ACE-2 interactions would allow a hyper-stimulation of FAAH activity, with a consequent failure in ECS function, which has been proven to predispose to cardiopulmonary complications.
My case probably only differs in that I have a testicular FAAH hyper-activation, which is primarily induced by sexual activity.
This of course leads to many concerns, of which vaccination is the most troubling. Does the provocation of the immune system lead to increased or decreased FAAH activity?
Do I have resistance to COVID-19 owing to an already high level of FAAH and systemic tolerance to it or is it extremely lethal for me regardless? Do I have a chance armed with loads of FAAH inhibitors or is all resistance futile?
https://www.researchgate.net/profile/Francesco-Pelizzoni/publication/344742444_Coronavirus-induced_severe_acute_respiratory_syndrome_sars_as_a_possibile_expression_of_fatty_acid_amide_hydrolase_faah_hyper-_activation_and_possible_therapeutic_role_of_faah_inhibitors_in_covid19-in/links/5f8d4da4a6fdccfd7b6c0854/Coronavirus-induced-severe-acute-respiratory-syndrome-sars-as-a-possibile-expression-of-fatty-acid-amide-hydrolase-faah-hyper-activation-and-possible-therapeutic-role-of-faah-inhibitors-in-covid19-in.pdf

Navigation

[0] Message Index

[#] Next page