Author Topic: FAAH Inhibitors  (Read 314 times)


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FAAH Inhibitors
« on: March 01, 2021, 03:31:09 PM »
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.

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.

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!?

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.

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.

Different natural compounds are natural inhibitors of FAAH in vitro. They include some flavonoids such as kaempferol, apigenin, luteolin, quercetin, myricetin and genistein.

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.

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).
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.

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.

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.

Psoralea corylifolia has many beneficial health effects, but some rather worrying adverse effects too.

Neobavaisoflavone is also a potential anti-COVID-19 drug agent.

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.

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.

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.

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.
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.

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?).

Anandamide can be metabolized by cyclooxygenase-2 (COX-2) to produce prostaglandin E2 (PGE2) ethanolamide.

Ibuprofen is also a FAAH inhibitor.

Cholesterol increases the substrate accessibility of FAAH.
This probably has something to do with vitamin D supplementation.

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.

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.

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.
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.
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.

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.

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.
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.
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.

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.

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.

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.

It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.

CBG is an inhibitor for the uptake of the endocannabinoid ligand anandamide.

Cannabinoids can suppress inflammation and cytokine storm in ARDS in relation to COVID-19.

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.

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.

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.

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.

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.

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.

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.

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.
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.

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.

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.

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.
« Last Edit: March 02, 2021, 12:23:31 PM by Progecitor »


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Re: FAAH Inhibitors
« Reply #1 on: March 01, 2021, 04:11:38 PM »
Can you put the font size in normal size please - you're clogging up the recent posts feed....


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Re: FAAH Inhibitors
« Reply #2 on: March 02, 2021, 01:02:10 PM »
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.

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?!)
My Protocol with adaoptogens, neurotransmitter precursors, energy production supplements helps with 80% of the symptoms with intercourse, 50% with masturbation.


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Re: FAAH Inhibitors
« Reply #3 on: March 02, 2021, 04:57:01 PM »
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.

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.
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).

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.

Check out Table 1. which contains a good list of medicinal plants with high quercetin content.

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.

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.

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.
(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.


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Re: FAAH Inhibitors
« Reply #4 on: March 03, 2021, 05:22:44 PM »
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?


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Re: FAAH Inhibitors
« Reply #5 on: March 04, 2021, 04:09:45 AM »
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?
When I was sick with this cold in 2020 February I had two orgasms and one nocturnal emission with zero POIS symptoms so there must be something immunity related to the POIS


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Re: FAAH Inhibitors
« Reply #6 on: March 04, 2021, 02:36:04 PM »
This could be the reason why FAAH inhibitors in themselves have a reduced effect. This pairing seems to counteract the rewarding effects of sexual activity too and I really felt reduced pleasure from masturbation. I think this could also counteract premature ejaculation (PE).
Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction
Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. This review considers recent research on the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that at least one FAAH-inhibiting drug (URB597) has been found to have potentially beneficial effects but no indication of liability for abuse or dependence. Although these areas of research are new, the preliminary evidence indicates that they might lead to improved therapeutic interventions and a better understanding of the brain mechanisms underlying addiction and memory.


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Re: FAAH Inhibitors
« Reply #7 on: March 07, 2021, 03:48:49 PM »
I have made lists from PPARG agonists and antagonists, but it looks like the effect is not dependent on the group the compound belongs to. It is also interesting to note that among these are also the ones that enhance my POIS. I haven't achieved a perfect conclusion yet, but the most important thing for a compound to be effective in my case is probably that it should both inhibit FAAH and activate PPARG at the same time. Pure PPARG agonists probably all enhance my case, although they seem to help other POISers nonetheless. Pure PPARG antagonists may also help me, but some of them still has to be tested for a reliable conclusion. Pure FAAH inhibitors also seem to work without serious side effects, but their efficacy is lower than those combined with PPARG agonism.

I think this article provides the most reliable information about combined FAAH inhibitors and PPARG agonist.
It is important to note that, among NAEs, AEA, OEA, and PEA all act as PPARA agonists, while only AEA is also capable of acting as a PPARG agonist.
The pharmacological inhibition of FAAH results in an enhancement of the endocannabinoid tone, which has many potential advantages as a therapeutic strategy, since the ECS is essential to many physiological processes in the central nervous system (CNS) and is usually upregulated as a protective response to various pathological conditions, such as pain, inflammation and the expansion of neoplastic clones.
The overlap between endocannabinoid and PPAR signaling suggests that it is possible to expand the activity profile of PPAR ligands by coupling their activity with the inhibition of enzymes such as FAAH. The applications of such an activity profile would be many, including the treatment of cancer, of neurodegenerative diseases, and of alcohol withdrawal, other than metabolic syndrome. In this particular case, the anti-inflammatory effects linked to endocannabinoid activation would be particularly helpful in reducing the hyperinflammatory state of metabolic syndrome patients; it is however important to note that PPARs themselves are among the most important mediators of such effects.
The activation of PPARA mediated by a stable analog of OEA could alleviate the symptoms of nicotine abstinence and reduce the reward mechanisms linked to its consumption, while PPARG activation can reduce the reward mechanisms linked to alcohol consumption.
While most of these compounds showed no relevant activity towards FAAH, some of them showed promising results; these were compounds 4, 5, 8, and 12 (resveratrol). In particular, this last compound can interact with PPARG, albeit as an antagonist and has numerous other reported biological activities. It is worth noting that compounds 1 (Rosiglitazone), 2 (Wy 14,643), and 3 (L165,041) showed little to no activity on FAAH, demonstrating that a more specific drug design process is necessary for the obtainment of dual-acting compounds. These biological results are reported in Table 1.
Rosmarinic acid was reported in the literature as a PPARG agonist and presents some structural similarity to arylacetic acids. Although we did not find any activity of this compound on either PPARA or PPARG, in light of its positive result as an inhibitor of FAAH, we decided to synthesize a short series of new derivatives of this compound and its natural analogue clovamide.

So a list I had found for PPARG agonists: arachidonic acid, several ligands like fatty acids (linoleic acid being the most common), Berberine (Berberis vulgaris), Cannabidiol, Daidzein (alfalfa), Genistein (soybean, chickpeas), Ibuprofen (only weakly), 15-HETE, biotin, taurine, curcumin, DHA, EPA, carvacrol (thyme and oregano), capsaicin (hot pepper), carnosic acid and carnosol (rosemary and sage), punicic acid (pomegrenate seed oil), citral (lemongrass), Cistus salviflius, synthetic thiazolidinediones (TZD) used to treat diabetes: troglitazone (Rezulin), pioglitazone (Actos), rosiglitazone (Avondia), tesaglitazar, chromium histidine, exercise, stilbenoid resveratrol, luteolin, epigallocatechin-3-gallate (EGCG) and others.
These may all work for one group (e.g. taurine), but I could be wrong. I also haven’t tested them all, but most of them make me more ill. I have just made some lemongrass tea (citral) and consumed about 1 liter. After about 3 hours it gave me a severe burning flatulence, which is rather strange as citral is not only a PPARG agonist, but also a weak TRPV1 antagonist too.
To the contrary ibuprofen [200 mg] actually seems to work, although with a weak efficacy. It didn’t give any burning pain, but it also didn’t relieve the mind fog. It takes a long time for a general effect to appear. Next time I will try a greater dose [400 mg].
Daidzein and Genistein both activate PPARG and inhibit FAAH, so they are prospective compounds.

The few PPARG antagonists I found are: green tea, black tea, astaxanthin, rosmarinus (carnosic acid), tamoxifen (also an estrogen receptor antagonist), resveratrol, apigenin, betulinic acid.
I think both black and green tea makes me better slightly. Astaxanthine seems to have worked for other POISers, but it is not very cost-effective. I will really have to try this. Carnosic acid seems an odd one compared to the other list, but a paper explicitly claims that it is an antagonist, although carnosol is still an agonist. Rosemary also contains rosmarinic acid which seems to be a pure FAAH inhibitor. It also contains betulinic acid which is another PPARG antagonist. Tamoxifen is used to treat breast cancer, so it would sound strange if I wanted a prescription for it, although I have POIS related nodules in my breasts. Resveratrol is also indicated as both an agonist and an antagonist. I think researchers should really address this issue to clarify the matter.

The papers also imply that mu opioid agonists could work in cannabinoid deprivation. Based on what I had written earlier in the Kappa agony thread it doesn't seem likely. As opioid alkaloids (probably papaverine) in poppy seed enhance my symptoms it is only logical to assume that opioid antagonists like Low Dose Naltrexon (LDN) would help me. Naltrexon also had efficacy in the treatment of COVID-19 and it simply can't be a coincidence.

The other things I tried in the meanwhile:
Lime tea (Tilia) [kaempferol – leaves and flower combined]: I consumed more than 1 liter. It definitely has a positive effect, although rather weak. It didn't really do anything to cognitive symptoms, but it had a soothing effect on the intestine almost without any flatulence.
I took a pill of vitamin B6 (pyridoxine) and I think it reduced POIS somewhat, but I was not feeling well (not the POIS way). I think it did something to my blood pressure, but I will have to test this out more.

Kaempferol, quercetin, and stilbenoid resveratrol are PPARG agonists.

The controversy of PPARG agonism or antagonism may be solved by a different approach.
The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPARG). Flavonoids are extensively metabolized during and after uptake and there is little known on the biological effects of these conjugated metabolites of flavonoids that are found in plasma. To investigate the effect of glucuronidation on the ability of flavonoids to activate PPARG we studied and compared the activity of quercetin, kaempferol and their relevant plasma conjugates quercetin-3-O-glucuronide (Q3G) and kaempferol-3-O-glucuronide (K3G) on different PPARG related endpoints.
It is concluded that flavonoids affect PPARG mediated gene transcription by a mode of action different from agonist binding. Increases in PPARG receptor mRNA expression and synergistic effects with endogenous PPARG agonists may play a role in this alternative mode of action. Glucuronidation reduced the activity of the flavonoid aglycones.!divAbstract

Some information about rosmarinic acid (FAAH inhibitor):
Although some of these enhance POIS, but it is probably caused by another compound like carnosol or carvacrol.
Rosmarinic acid accumulation is shown in hornworts, in the fern family Blechnaceae and in species of several orders of mono- and dicotyledonous angiosperms.
It is found most notably in many Lamiaceae (dicotyledons in the order Lamiales), especially in the subfamily Nepetoideae. It is found in species used commonly as culinary herbs such as Ocimum basilicum (basil), Ocimum tenuiflorum (holy basil), Melissa officinalis (lemon balm), Rosmarinus officinalis (rosemary), Origanum majorana (marjoram), Salvia officinalis (sage), thyme and peppermint. It is also found in plants in the family Marantaceae (monocotyledons in the order Zingiberales) such as species in the genera Maranta (Maranta leuconeura, Maranta depressa) and Thalia (Thalia geniculata).
Rosmarinic acid and the derivative rosmarinic acid 3'-O-?-D-glucoside can be found in Anthoceros agrestis, a hornwort (Anthocerotophyta).

Rosemary contains a number of phytochemicals, including rosmarinic acid, camphor, caffeic acid, ursolic acid, betulinic acid, carnosic acid, and carnosol. Rosemary essential oil contains 10–20% camphor.

Genistein (4',5,7-trihydroxyisoflavone) is an isoflavone. Soybean, a high protein vegetable, has been accounted for to contain the most genistein. Pint sized quantities of genistein are found in different legumes, for example, chickpeas (garbanzo beans). Soy based edibles contain genistein in variable quantity. Other plant foods that have been shown to contain genistein consist of alfalfa and clover sprouts, barley meal, broccoli, cauliflower and sunflower, caraway, and clover seeds.
Genistein is also a proposed drug in the treatment of Alzheimer's disease.

As I have a possible arachidonic acid overload PPARG is probably over-activated all the time.
Peroxisome proliferator-activated receptor-gamma (PPARG) modulates the expression of many genes actively involved in regulating the cell cycle. Specific ligands bind PPARG protein can exert inhibition on the proliferation of human breast carcinoma cells. In contrast, the persistent over-regulation of the PPARG gene can also increase the likelihood of breast carcinogenesis.

Macamides are neuroprotective and they can activate PPARG.
The gene reporter assay was performed to test the ability of macamides to activate PPARG receptors. No PPARG activation was observed in response to MAC 18:1 exposure. However, MAC 18:2 and MAC 18:3 at 30 uM activated PPARG with EC50 values of 22.6 ± 0.1 uM and 20.4 ± 0.1 uM, respectively (p ? 0.05). Human PPARG activation was observed in the presence of RGZ, with an EC50 value of 240.8 ± 1.4 nM.
Macamides, as they are structurally similar to AEA, should activate PPAR, particularly the PPAR? receptor.
This observation is in agreement with results of a study which describes linoleic acid and linolenic acid as endogenous activators of PPARG, with EC50 values in the range of 5–20 uM. Therefore, the presence of the linoleic and linolenic acid backbones in macamides MAC 18:2 and MAC 18:3 makes these compounds suitable ligands for PPARG transactivation. This result is considered important in the study of the relationship between macamides and AEA. Moreover, it will be interesting to examine the effects of macamides that are mediated by PPARG.

An extensive study about the relation of cannabinoids and PPARs

The severe adverse effects of thiazolidinediones which led to their withdrawal from the market or restricted clinical application are suggested to be a result of full PPAR? activation, contrasting the weak agonistic effect of endogenous PPARG ligands such as fatty acids and prostanoids.
Noteworthy, along with plants and mushrooms applied in traditional medicines, PPARG-ligands were often identified in plants that are common food sources, including the tea plant (Camellia sinensis), soybeans (Glycine max), palm oil (Elaeis guineensis), ginger (Zingiber officinale), grapes and wine (Vitis vinifera), and a number of culinary herbs and spices (e.g. Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris).
Although most of the agonists identified in food sources are weak PPARG agonists per se, the effects of their metabolites deserve further research to better estimate their preventive potential. While research in this direction is largely missing, a previous study reported that some main metabolites of flavonoid constituents from red clover (Trifolium pratense) have an up to 100-fold higher PPARG binding affinity than their precursors.

Check out Table 1. as it lists a lot of PPARG ligands which could potentially modify POIS.
You better check the table as I only dumped this here for easier search.
The list: Amorpha fruticosa L. - Amorfrutins (in the fruits), Astragalus membranaceus Moench - Formononetin (in ethanolic extracts), Bixa orellana L. - Bixin and norbixin (in annatto extracts), Camellia sinensis - Catechin (in green tea), Cannabis sativa L. - THC, Chromolaena odorata - (9S,13R)-12-Oxo-phytodienoic acid and odarotin, Coix lacryma-jobi var. ma-yuen - Hydroxy unsaturated fatty acids, Commiphora mukul - Commipheric acid, Cornus alternifolia L.f. - Kaempferol-3-O-B-glucopyranoside, Cymbopogon citratus - Citral (in lemongrass oil), Echinacea purpurea (L.) - Alkamides, Elaeis guineensis Jacq. - Tocotrienols (in palm oil), Elephantopus scaber L. - Deoxyelephantopin, Epimedium elatum C. - Acylated flavonol glycosides, Euonymus alatus - Kaempferol and quercetin, Glycine max (L.) - Genistein (in soya beans); Glycyrrhiza glabra L. - 5?-Formylglabridin, (2R,3R)-3,4',7-trihydroxy-3'-prenylflavane, echinatin, (3R)-2',3',7-trihydroxy-4'- methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, glabrone; Glycyrrhiza foetida Desf. - Amorfrutins (in the edible roots), Glycyrrhiza inflata Batalin - Licochalcone E (in roots), Glycyrrhiza uralensis Fisch. ex DC. - Flavonoids and 3-arylcoumarins (in ethanolic extract of the roots), Limnocitrus littoralis (Miq.) Swingle – Meranzin, Lycium chinense Mill. - Fatty acids (in root bark), Magnolia officinalis – Magnolol and honokiol, Melampyrum pratense L. - Lunularin and fatty acids, Momordica charantia L. - Cucurbitane-type triterpene glycosides, Notopterygium incisum C.T. - Polyacetylenes, Origanum vulgare L. - Biochanin A, Panax ginseng - Ginsenoside 20(S)-protopanaxatriol and ginsenoside Rb1 (in ginseng roots), Pinellia ternata - Fatty acids (in different apolar extracts from the rhizomes), Pistacia lentiscus L. - Oleanonic acid, Pseudolarix amabilis - Pseudolaric acid B, Pueraria thomsonii Benth – Daidzein, Robinia pseudoacacia var. umbraculifer DC. - Amorphastilbol, Rosmarinus officinalis L. - Carnosic acid and carnosol, Salvia officinalis L. - Carnosic acid and carnosol (in ethanolic extract of sage); as well as 12-O-methyl carnosic acid and ?-linolenic acid, Sambucus nigra L. - ?-Linolenic acid, linoleic acid, and naringenin, Saururus chinensis - Saurufuran A (in roots), Silybum marianum (L.) - Isosilybin A (in silymarin, a phenolic mixture from the fruits of the plant), Terminalia bellerica Roxb. - Gallotannins (in the fruits), Thymus vulgaris L. - Carvacrol (in thyme oil), Trifolium pratense L. - Isoflavones (in red clover extracts), Vitis vinifera L. - Ellagic acid, epicatechin gallate, flavonoids (in grapes and wine), Wolfiporia extensa - Dehydrotrametenolic acid (in dried sclerotia), Zingiber officinale Roscoe - 6-Shogaol (in ginger roots).

In this study, PPAR activation by oregano (e.g., Origanum vulgare) and its components was tested. Oregano extracts bind but do not transactivate PPARG, and binding affinity differs among different oregano extracts. The extracts contain PPARG antagonists (e.g., quercetin, luteolin, rosmarinic acid, and diosmetin), selective PPARG modulators (e.g., naringenin and apigenin), and PPARG agonists (e.g., biochanin A). Oregano extract and isolated compounds in the extract antagonize rosiglitazone-mediated DRIP205/TRAP220 recruitment to PPARG, pointing to oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARA agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis.

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPARG), a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPARG also represses the inflammatory process. Similarly, the PPARG agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPARG, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPARG activation.
Table 1. contains other PPARG agonists like DHA, EPA, curcumin, capsaicin, punicic acid.

EPA and DHA also inhibit COX!
EPA and DHA provided by the diet or arising from a-linolenic acid metabolism inhibit adenylate cyclase and COX activities, presumably altering adipogenesis.
Arachidonic acid (ARA) and some of its metabolites generated through cyclo-oxygenase (COX) and lipoxygenase activities are implicated in adipogenesis as activators/ligands of PPARs. Thus ARA is a potent stimulator of adipogenesis that acts through cell-surface IP-R and nuclear PPAR in early and late events of adipogenesis, respectively.
By the way at the time I drank a lot of Cistus incantus tea (approximately 1 liter) besides heart ache or heartburn I noticed other symptoms. I also felt my chest constricted and had an inflammation at the descending colon. I will have to test it again to see if these symptoms can be reproduced.
I also bought some naproxen, but haven't tested it yet.

For those POISers who have emotional problems this may be interesting.
A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity.

Inhibition of FAAH may increase regeneration through PPARA.

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.
Some studies suggested that the immunomodulatory activity of saffron may involve direct targeting of Toll-like receptors (TLRs), attributed to the regulation of various transcription factors such as nuclear factor (NF-kB), activator protein 1 (AP-1) and also their downstream signaling pathways. TLRs play a crucial role in the innate immune system by triggering pro-inflammatory signaling pathways in response to either external or internal stimuli. Moreover, NF-kB acts a vital role in producing pro-inflammatory cytokines such as IL-1, IL-2 and IFN-g in T lymphocytes. Pradere et al. showed saffron has an inhibitory effect on producing pro-inflammatory cytokines like IL-1 production by suppressing NF-kB activity via the inhibition of I kappa B kinase-a (IKK-a) phosphorylation and prevention of nuclear translocation of the NF-kB p65 subunit.

Until the BIA 10–2474 case is resolved there won't be any pharmaceutical FAAH inhibitors.
It is expected that the effects of FAAH inhibitors, due to their pharmacological interaction with the endocannabinoid system, may exhibit tolerance following repeated administration. This phenomenon is called tachyphylaxis.
This is probably the reason why herbal teas and other supplements lose efficacy over time.

Endocannabinoids have an intricate connection to helminthic infections and this may also be the reason why ivermectin could work in parasitic infections, COVID-19 infections and possibly in POIS as well.
AEA was also reported as immunosuppressive to adaptive cells such as T and B lymphocytes. It is believed that AEA functions this way by signaling via CB2 receptor, PPARG and by inhibiting NF-kB. Similar to innate cells, AEA inhibits lymphoid cell proliferation, Th1 cytokine production and enhances Th2 responses by increasing expression of IL-4 and IL-10. Similarly, 2-AG (more precisely a 2-AG metabolite) was immunosuppressive towards T cells by impairing pro-inflammatory IL-2 cytokine expression.
Although eCBs at times play controversial roles in immune responses, in general, eCBs are immunosuppressive, with AEA being the most potent. Interestingly, the Th1 response
inhibition by eCB is coupled with enhancement of Th2 response in many immune cells types.
Moreover, Th1 cytokine production was associated with reduced FAAH (AEA degrading enzyme) activity suggesting that a self-sustaining anti-inflammatory mechanism of eCBs.
Therefore, eCBs can be exploited for their anti-inflammatory therapeutic potential.
Endocannabinoids are lipid signaling molecules that have functions in dampening Th1 immune responses and driving Th2 immunity.

Peroxisome proliferator-activated receptor gamma (PPARG), insulin receptor substrate-1 (IRS-1) and nuclear transcription factor kappa B (NF-kB) are important biomarkers involved in numerous metabolic processes. PPARG plays a key role in regulating lipid, carbohydrate, glucose and insulin metabolisms. It has been shown that exercise induced an increase in PPARG expression in liver and skeletal muscle tissues. In the current study, PPARG expression levels in the liver and muscle tissues were significantly elevated compared to the control group. Remarkably, CrHis and biotin supplementation significantly increased PPARG expression levels in sedentary and exercised rats. The efficacy of CrHis and biotin was more pronounced when used simultaneously, thus indicating a synergetic effect. Our previous findings demonstrated that CrPic and biotin, as well as their combination, increased PPARG expression in adipose tissue and improved insulin resistance in type 2 diabetes rats.

PPARG may be an important molecule in acne vulgaris, the most frequent sebaceous dermatoses (SG)-related dermatosis with abnormal lipid storage and inflammation. Arachidonic acid (AA) markedly enhances lipid synthesis in SZ95 sebocytes, and some of this induction might be regulated via PPARG.
In summary, our study provides evidence that PPARG participates in the signaling mechanisms of sebocyte differentiation. We also demonstrated that AA-activated PPARG is involved in the regulation of major neutral lipid and phospholipid biosynthesis. Finally, we presented that PPARG is activated by AA keto-metabolites (5-KETE, 12-KETE). Taken together, our data implicate that AA-activated PPARG is an important regulator of differentiation and lipid metabolism in human sebocytes; therefore PPARG might be a potential therapeutic target molecule in sebaceous dermatoses.

Ketoconazole (Nisoral) is also a FAAH inhibitor. I have been using it effectively for years as a means to control POIS induced dandruff formation. This is probably in line with the former article as I also have more acne after O. I think this also contradicts a possible fungal origin even though they may still be present. I think this is something similar to my case with dysbacteriosis.
I also have to wonder if ketoconazole pills could be effective, although they may have serious side effects on the long run. Still it would be good to know as there is a possibility that it could work very well in the treatment of COVID-19 infection.
In the present study we have demonstrated that ketoconazole (Nisoral) inhibits the uptake of the endocannabinoid AEA into a variety of cell lines, and that this effect can be most simply explanined by the ability of the compound to inhibit FAAH.
In Sweden, ketoconazole is available as a shampoo (20 mg/ml) and until recently as tablets (200 mg; the dose could be doubled if deemed necessary).
In intact rat peritoneal polymorphonucelar leukocytes, leukotriene B4 and 5-hydroxyeicosatetraenoic acid production from arachidonic acid was inhibited with IC50 values of 30 and 26 µM, respectively. These authors demonstrated further than oral pretreatment with ketoconazole (10–40 mg/kg) inhibited in a dose-dependent manner ovalbumin-induced bronchoconstriction in sensitised guinea pigs, suggesting that leukotriene synthesis could be inhibited in vivo by the compound.

Carpofen (NSAID) is a FAAH inhibitor. Caprofen is a COX inhibitor too.
Membrane lipids could also modulate structure, functional activity, and subcellular localization of FAAH. Indeed, the FAAH dimer is stabilized by the lipid bilayer and shows a higher membrane-binding affinity and enzymatic activity within membranes containing both cholesterol and the FAAH substrate, AEA. In addition, the colocalization of cholesterol, AEA, and FAAH in intact cells supports a mechanism by which cholesterol can increase substrate accessibility to the active site.

Table 1 contains a lot of herbs with a high quercetin content.

Apigenin reduces PPAR-gamma expression.
Further studies suggest that apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target gene cluster of differentiation 36 (CD36). The reduced CD36 expression in adipocytes reduces the expression of peroxisome proliferator-activated receptor gamma (PPARG) which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPARG expressions and inhibits adipocyte differentiation; overexpression of constitutive active STAT3 reverses the apigenin-inhibited adipogenesis. Taken together, our data suggest that apigenin inhibits adipogenesis via the STAT3/CD36 axis. Our study has delineated the mechanism of action underlying the anti-visceral obesity effect of apigenin, and provide scientific evidence to support the development of apigenin as anti-visceral obesity therapeutic agent.

Relora containing Magnolia officinalis bark also helped some POISers.
In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20–60 uM) dose-dependently enhanced the activity and intracellular level of PPAR-B/G in platelets.
Additionally, magnolol significantly inhibited collagen-induced PKCa activation through a PPAR-B/G and PKCa interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B2 formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol.

PPAR agonists reduce voluntary alcohol consumption in rodent models.

The cardinal biologic activity of PPARG is the induction of differentiation of adipocytes, the cell type that expresses the highest levels of PPARG amongst normal tissues. Lower levels of PPARG are, however, found in other normal tissues and cell types such as skeletal muscle, liver, breast, prostate, colon, type 2 alveolar pneumocytes, some endothelial cells as well as monocytes, and B-lymphocytes.
Also, uncertainty about mechanisms of anticancer effects of PPARG ligands has resulted from variability in the classification of some compounds (e.g., bisphenol A diglycidyl ether [BADGE], which has been shown to have both agonist and antagonist activities).
Also, the observation that combinations of PPARG agonist and antagonist compounds result in additive antiproliferative effects in various cancer cell lines is consistent with this mechanism. This mechanism is plausible, as it has been shown to inhibit the NF-kB signaling pathway, which is central to inflammation and to the proliferation and survival of multiple cancer types including hepatocellular and colon carcinomas as well as multiple myeloma.

As betaine was mentioned a lot on the site I thought this may have relevance.
Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.
Betaine, a methyl donor, is a naturally occurring compound in common foods, such as wheat bran, wheat germ, spinach, pretzels, shrimp and wheat bread etc. In vivo, betaine can also be produced by oxidation of choline, and it serves as an effective methyl donor for remethylating homocysteine (Hcy) into methionine (Met).

An extensive overview of the complex relation of cannabinoids and PPARs.

Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat.
The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function.
We used transactivation assays to show that CA has a PPARA/G antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.
Mammalian adipose organs can be divided into two distinct types of adipose tissues: white and brown. White adipose tissue (WAT) is specialized in the storage and release of fatty acids, which are required as an energy source for heart and muscles. In contrast, brown adipose tissue (BAT) dissipates energy in the form of heat by uncoupling the mitochondrial respiratory chain from ATP synthesis. Adipose tissue is the largest endocrine organ and links metabolism and immunity. It is a major actor in the regulation of energetic metabolism and represents a potential therapeutic target to combat fat mass disorders such as obesity and hypermetabolism in critical illness.
High increases in catecholamine production, such as epinephrine and norepinephrine, and pro-inflammatory factors are observed in critical illness, but pharmacologic treatments are associated with secondary effects such as gastrointestinal and cardiovascular failures. Obesity appears to be protective against death induced by critical illness, and this process is called the "obesity paradox".
Carnosic acid (CA) inhibits the browning process of human white adipocytes.
Under conditions where browning of white adipocytes is exacerbated, such as in critical illness after a severe burn injury or cachexia, CA treatment may represent a potential therapeutic option. Animal models and patients with severe burns develop hypermetabolism with massive browning of white adipose tissue, hepatic steatosis, and cachexia, which are harmful and have limited therapeutic treatments. In a similar manner, cancer-associated cachexia, a wasting syndrome, is associated with increased browning of white adipose tissue, which leads to higher thermogenesis with increased lipid mobilization and energy expenditure, further worsening the clinical situation and risk of death. Inhibition of white adipose tissue browning in burn and cancer patients represents a promising approach that can be potentially achieved with CA treatment alone or in combination with other approaches. In line with this, it has been suggested that CA is efficient against obesity-associated cancers, in particular against colon cancer. Furthermore, it is known that PPAR activation by thiazolidinediones is associated with bone fracture, and we could speculate that CA treatment has the potential to restore bone mass, given that betulinic acid, a PPARG antagonist, is known to favor osteogenesis at the expense of adipogenesis.

Betulinic acid
It exhibits anti-HIV, antimalarial, antineoplastic and anti-inflammatory properties.
The effects of betulinic acid as an anticancer agent in breast cancer is found to be cannabinoid receptor dependent. Betulinic acid behaves as a CB1 antagonist and CB2 agonist.

Bitter melon up-regulates PPARG.
It would be interesting to test Momordica charantia also called bitter melon or bitter gourd. It has anti-diabetic, anti-HIV, anti-ulcer, anti-inflammatory, anti-leukemic, anti-microbial, and anti-tumor effects.


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Re: FAAH Inhibitors
« Reply #8 on: April 13, 2021, 02:47:03 PM »
I wanted to do a post about the possible connection between infections and the endocannabinoid system before I caught COVID-19. Unfortunately I couldn't judge if there is a link to my POIS, however the theoretical background still seems credible.
Aberrant activation of toll-like receptors (TLR) probably have a role in post-covid syndrome and possibly in POIS as well.

Aberrant activation of toll-like receptor (TLR)s results in persistent and prolonged neuroinflammation and has been implicated in the pathogenesis and exacerbation of psychiatric and neurodegenerative disorders. TLR3 coordinates the innate immune response to viral infection and recent data have demonstrated that inhibiting fatty acid amide hydrolase (FAAH), the enzyme that primarily metabolizes anandamide, modulates TLR3-mediated neuroinflammation.
(TLR)3 activation results in the induction of type 1 interferon (IFN-A and IFN-B) and NFkB-inducible (e.g. IL-1B, IL-6 and TNF-a) 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.
The FAAH substrates AEA, OEA and PEA have been shown to modulate TLR4-induced thermoregulatory changes and hypophagia most likely mediated via modulation of hypothalamic cytokine expression. A recent study from our group demonstrated that FAAH inhibition modulated TLR4-mediated neuroinflammatory responses in the hippocampus and frontal cortex, an effect which was accompanied by an attenuation of TLR4-mediated anhedonia, but not sickness behaviour. Furthermore, FAAH inhibition has been demonstrated to reverse TLR4-mediated mechanical allodynia, thermal hyperalgesia and paw oedema.
The results of the present study demonstrate that the systemic administration of the FAAH inhibitor URB597 (FAAH inhibitor) attenuated TLR3-mediated microglia/macrophage activation and some, but not all, associated behavioural changes in female rats.

Toll?like receptor (TLR)3 is a key component of the innate immune response to viral infection.
The data revealed that TLR3?induced expression of interferon? or NFkB?inducible genes (IFN?a/B, IP?10, or TNF?a), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3?induced IFN?a expression in the spleen of female, but not male, rats 8 hr post TLR3 activation. Furthermore, TLR3 activation increased plasma corticosterone levels, induced fever, and reduced locomotor activity and body weight — effects independent of sex.
Systemic administration of the monoacylglycerol lipase (MAGL) inhibitor MJN110 and subsequent increases in 2?AG levels did not alter the TLR3?induced increase in IP?10, IRF7, or TNF?a expression in the spleen or the hypothalamus of male or female rats. In contrast, the fatty acid amide hydrolase (FAAH) inhibitor URB597 increased levels of AEA and related N?acylethanolamines, an effect associated with the attenuation of TLR3?induced inflammatory responses in the hypothalamus, but not the spleen, of male and female rats.

Recent studies performed in animal models of acute and chronic pancreatitis have shown that the stimulation of primary afferent capsaicin-sensitive neurons or treatment with peptides (e.g., calcitonin gene-related peptide) before the exposure to harmful factors, can activate an adaptive mechanism called "preconditioning" which is able to reduce pancreatitis development. Sensory neurons are involved in gastroprotection and regulation of visceral blood flow and their stimulation by capsaicin can potentially inhibit the progression of inflammation, by improving the endogenous release of nitric oxide (NO) and thus the pancreatic blood flow. Certain psychoactive molecules can modulate the endocannabinoid system in the gut and possibly impact the pathogenesis of inflammatory bowel disease, as well as its extra intestinal manifestations such as pancreatitis. Anandamide reduces mucosal oxidative stress, inhibits the inflammatory process and preserves the integrity of gastric mucosa in stress-induced gastric ulcers.
On the contrary, the intracellular TLRs, expressed in cell endosomes, detect microbial nucleic acids, specifically viral double-strand RNAs (TLR3).
More and more studies have focused their attention on the role that TLRs may play in neurodegeneration, considering that they are extensively expressed in immune and non-immune cells and their expression can change not only during microbial infections but also in the presence of sterile inflammation when the pathogens are absent.
High levels of polyunsaturated fatty acids (PUFA), such as the omega-3 fatty acid docosahexaenoic (DHA), have been shown to induce anti-inflammatory effects and reduce mitochondrial dysfunction-mediated motor symptoms together with decreasing alpha-synuclein accumulation and inflammation in PD animal models. DHA inhibits, whereas saturated fatty acids can activate, certain TLR-mediated pro-inflammatory signaling pathways. DHA blocks the activation of TLR4 and TLR2/1 or TLR2/6 and other TLRs in an indirect manner, targeting TLRs downstream pathways during the receptor dimerization process (e.g., lipid rafts). Overall these findings highlight the involvement of diet, such as the intake of saturated fatty acids and DHA, in the modulation of TLR signaling pathways and related involvement in chronic inflammation and subsequent risk of chronic diseases. An in-vitro study has shown that an extract of Panax notoginseng was able to suppress microglial activation and decrease the release of inflammatory factors (IL-6 and TNF-a), suggesting the potential therapeutic utility in slowing down PD progression. The flavonoid silymarin, extracted from the seeds and fruit of Silybum marianum, was found to exert neuroprotective effects in 6-OHDA-induced hemi-parkinsonian rats, through the alleviation of nigral injury, the increase of anti-oxidant defenses and suppression of TLR4 activation.

PPARG is expressed in various immune cells, such as primary peritoneal macrophages, dendritic cells, and T cells. Growing evidence supports an anti-inflammatory role for PPARG. Activation of PPARG by various ligands down-regulates the synthesis and release of proinflammatory cytokines. For example, PPARG ligands inhibit the expression of iNOS and TNF-a downstream of TLRs by ligand-dependent transrepression in macrophages. Therefore, PPARG ligands may be important anti-inflammatory agents to treat inflammation related diseases. Varieties of endogenous and synthetic ligands bind to PPARG to modulate gene expression.
PPARG agonists negatively regulate TLR3- and TLR4-induced IFN-B production in macrophages.
Activation of PPARG by various ligands down-regulates the synthesis and release of many cytokines from various cell types that participate in the inflammatory processes. In macrophages, PPARG-mediated repression of LPS-induced iNOS gene expression has been demonstrated. PPARG has been reported to regulate the expression of macrophage colony-stimulating factor in alveolar macrophages. PPARG agonist has been shown to down-regulate IL-17 expression in a murine model of allergic airway inflammation. PPARG is expressed in both murine CD4 and CD8 cells, and PPARG ligands directly decrease IFN-g expression in T cells. In dendritic cells, PPARG agonists have been shown to inhibit TLR-mediated activation of dendritic cell via the MAP kinase and NF-kB pathways. However, the effect of PPARG on IFN-B production downstream of TLR signaling has not been clarified. In this study, we show that PPARG agonists inhibit LPS and poly(I:C)-induced IFN-B transcription and protein secretion in vitro and in vivo. In particular, the PPARG agonist, troglitazone, impaired LPS and poly(I:C)-induced IRF3 binding to the IFN-B promoter. As a result, LPS and poly(I:C)-induced STAT1 phosphorylation and subsequent ISRE activation are inhibited by troglitazone. Considering the involvement of IFN-B in several pathogenic autoimmune diseases, our results suggest that PPARG agonists may have therapeutic potential to cure these diseases. In accordance with our results, recent studies have shown that PPARG agonists could ameliorate murine lupus in a mouse model of SLE.
The production of type I IFNs, including IFN-a and -B is central for the innate immune responses to eliminate viral and bacterial infection. At the same time, uncontrolled expression of type I IFNs has been found in diverse pathogenic autoimmune diseases, including systemic lupus erythematosus. Several pathogen recognition receptors, such as TLR3, TLR4, RIG-I, and MDA-5, recognize highly conserved microbial components and activate the regulatory pathways to coordinate the production of type I IFNs.
A variety of PPARG agonists have been demonstrated to have anti-inflammatory functions, including endogenous ligands such as 15d-PGJ2 and synthetic ligands such as troglitazone and rosiglitazone.
In conclusion, our results show that PPARG agonists inhibited LPS and poly(I:C)-induced IFN-B transcription and secretion in vivo and in vitro. Furthermore, we show that troglitazone treatment prevented IRF3 binding to the IFN-B promoter. As a result, LPS and poly(I:C)-induced STAT1 phosphorylation and subsequent ISRE activation were inhibited by troglitazone. These results demonstrate that PPARG negatively regulates IFN-B production in TLR3- and -4-stimulated macrophages by preventing IRF3 binding to the IFN-B promoter. Our results provide a strategy to down-regulate IFN-B production downstream of pathogen recognition and suggest that PPARG agonists may have therapeutic potential in autoimmune diseases with uncontrolled IFN-B production.

We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signaling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signaling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialed in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.
TLR4 is important in initiating inflammatory responses, and its overstimulation can be detrimental leading to hyperinflammation. Dysregulation of TLR4 signaling has been shown to play a role in the initiation and/or progression of various diseases, such as ischaemia-reperfusion injury, atherosclerosis, hypertension, cancer, and neuropsychiatric and neurodegenerative disorders. Moreover, TLR4 is also important in the induction of the host immune response against infectious diseases such as bacterial, fungal and viral infections, and malaria.
Moreover, activation of TLR4 on platelets whether by PAMPs (viraemia and LPS) or DAMPs induces a prothrombotic and proinflammatory state, which provides a potential explanation for the thrombotic events (such as MI) observed in COVID-19 patients.
Furthermore, LPS causes septic cardiomyopathy via TLR4 activation, which is of relevance since sepsis—whether viral or bacterial—is implicated in severe cases of COVID-19.
The body needs a certain amount of TLR4 stimulation to fight the virus, but not an overstimulation, especially in the later stages. However, other TLRs will be able to produce some interferons if TLR4 is antagonised.
The potential use of glycyrrhizin for COVID-19 has been reviewed in detail by Murck et al. and Andersson et al. Glycyrrhizin is an active ingredient extracted from liquorice plant and has been used in traditional Chinese medicines to control COVID-19. It gets metabolized in the human gut to the systemically active metabolite glycyrrhetinic acid. It appears to possess direct antiviral properties and was reported to inhibit in vitro replication and penetration of SARS-CoV-1. More importantly, it has an anti-inflammatory effect through downregulation of HMGB1-mediated inflammation and TLR4 antagonism. Given its dual antiviral effects and TLR4 antagonism, as well as being a natural compound, it may be a promising candidate in the treatment of COVID-19.

MERS-CoV S glycoprotein induced the expression of the negative regulator of TLR signaling IRAK-M as well as of the transcriptional repressor PPARG. Inhibition of DPP4 by its inhibitor sitagliptin or siRNA abrogated the effects of MERS-CoV S glycoprotein on IRAK-M, PPARG and IL-10, confirming that its immunosuppressive effects were mediated by DPP4 receptor. The effect was observed both in THP-1 macrophages and human primary peripheral blood monocytes.
Earlier evidence has shown that lack of PPARG resulted in increased lethality in mice infected with Influenza virus, and in H3N2 influenza virus infection PPARG was induced via Fatty Acid Binding Protein 5 (FAPB5) to suppress immune responses, supporting the crosstalk of PPARG with viral infection and innate immune responses. A PPARG polymorphism (Pro12Ala) has been associated with sustained response to Hepatitis C Virus. Interleukin-1 Receptor Associated Kinase -M (IRAK-M) levels in peripheral monocytes and macrophages regulate inflammatory responses in humans and in alveolar macrophages but the effect of viral infection on IRAK-M expression has not been previously demonstrated. Analysis of genetic variants of IRAK-M has only been performed in association with Systemic Lupus Erythematosus, but no association was found. Thus, our results provide evidence for the crosstalk of IRAK-M and viral infection and support earlier findings on the effect of influenza viruses on PPARG expression and function.
The magnitude of macrophage activation is regulated by multiple factors including the transcription factor PPARG, which is known to suppress production of cytokines and IRAK-M, an inactive IRAK kinase isoform known to suppress TLR signaling.
In the present study, we demonstrated that the DPP4-binding protein of MERS-CoV, the S glycoprotein, altered macrophage responses rendering them hypo-responsive to TLR4 stimulation. This finding indicates that interaction of MERS-CoV S protein with DPP4 initiates signals that suppress macrophage activation supporting an immunomodulatory mechanism of MERS-CoV that may allow viral replication and expansion.
Macrophage activation is regulated at different levels and factors. IRAK-M is an inactive homolog of IRAK kinases and is known to suppress macrophage activation by TLRs thus rendering them hypo-responsive to pro-inflammatory triggers. Expression levels of IRAK-M highlight their responsiveness and are regulated by various factors including lung surfactants as well as TLR ligands and adipokines.
Responsiveness of macrophages is also regulated by the transcription factor PPARG, a transcriptional repressor that can suppress transcription of pro-inflammatory cytokines such as TNF-a and IL-6. Our results showed that MERS-CoV S glycoprotein induced the expression of PPARG providing an additional molecular mechanism for its immunosuppressive action. Given the fact that PPARG is expressed not only in macrophages but also in T-cells and epithelial cells, this mechanism may not be restricted to macrophages.
Our findings demonstrated that indeed the immunosuppressive action of the S glycoprotein is mediated by Dipeptidyl-Peptidase 4 (DPP4) since inhibition of DPP4 by sitagliptin, a DPP4 inhibitor, ameliorated induction of IRAK-M and PPARG. Sitagliptin and other DPP4 inhibitors are known to act as anti-diabetic agents reversing insulin resistance. It is yet unknown whether individuals that are under treatment with sitagliptin are less susceptible to MERS-CoV infection or whether they do not produce as severe symptoms of the disease. Moreover, our findings may propose the use of sitagliptin as a potential treatment of patients with MERS-CoV infection since it may reverse the immunosuppressive actions of the virus.

Toll-like receptors (TLRs) are key players in host defense, homeostasis and response to injury. However, uncontrolled and aberrant TLR activation has been proposed to trigger the onset of certain
psychiatric and neurodegenerative disorders and elicit detrimental effects on the progression and outcome of established disease. Furthermore, TLR-induced neuroinflammation results in a constellation of behavioural changes which include altered appetite, reduced mood, cognitive changes, anxiety and anhedonia (chronic unhappiness which is a main symptom of depression). Accumulating evidence demonstrates potent immunoregulatory effects of the endogenous cannabinoid (endocannabinoid) system, suggesting that this system may represent an important therapeutic target in disorders with a neuroinflammatory component. The most widely studied endocannabinoid, N-arachidonoyl ethanolamine (AEA, also referred to as anandamide), has been shown to modulate neuroimmune responses, including those induced following TLR activation, although the effects depend on conditions under investigation. For example, several in vitro studies have demonstrated that increasing AEA tone, directly or via inhibition of the primary enzyme responsible for its metabolism, the serine hydrolase fatty acid amide hydrolase (FAAH), is associated with attenuation of TLR4-induced production of pro-inflammatory cytokines and mediators such as TNFa, IL-1b, prostaglandins and nitric oxide, while concurrently increasing anti-inflammatory mediators such as IL-10. However, data also demonstrate an augmentation of TLR4-induced pro-inflammatory mediators such as IL-6 by AEA. While some studies have demonstrated anti-inflammatory effects of AEA on TLR4-induced inflammatory responses to be mediated by cannabinoid CB1 and/or CB2 receptor activation and consequential regulation of NFjB and MAPK activation, non-CB1/CB2 receptor mediated effects of AEA on inflammatory processes in vitro have also been reported. AEA also has affinity for and activity at additional receptor targets to CB1 and CB2 receptors, namely the peroxisome proliferator-activated receptors (PPARs), the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and also the novel cannabinoid receptor, G-protein coupled receptor (GPR)55 activity at which may account for the variability in the effects of AEA on neuroinflammatory responses following TLR activation. Similar to in vitro data, in vivo studies have also revealed modulation of TLR4-induced inflammatory responses by AEA. The proposed AEA reuptake inhibitor AM404 has been shown to attenuate TLR4-induced increases in plasma levels of IL-6 and IL-1b, the latter effect mediated by CB1 receptor activation. Furthermore, AM404 or enhancing AEA tone via pharmacological inhibition of FAAH, augmented TLR4-induced increases in plasma TNFa levels, an effect at least partially mediated via activation of PPARG. In the brain, AEA activation of hypothalamic CB1 receptors has been shown to facilitate, while antagonism of the central CB1 receptors attenuates, TLR4-induced increases in plasma TNFa levels. In addition, work from our laboratory has demonstrated that enhancing AEA levels following FAAH inhibition was associated with attenuation of TLR4-induced increases in IL-1b, and increases in expression of suppressor of cytokine signaling (SOCS3), in the hypothalamus. It should be noted that in addition to AEA, related fatty acid amides, N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), are also metabolised by (FAAH) and shown to be increased following FAAH inhibition. These N-acylethanolamines have been shown to exert potent biological effects on satiety, pain and inflammation and so it cannot be ruled out that some of the effects of FAAH inhibition may be due in part to activity of OEA or PEA, alone or in combination, with AEA. In addition to AEA, OEA has and increasing evidence supports an important physiological role for TRPV1 in the brain. Furthermore, FAAH inhibition can lead to indirect activation/desensitization of TRPV1 and subsequent analgesic effects, anti-inflammatory effects and central effects on mood.
The data demonstrate that the effect of FAAH inhibition on neuroinflammation is mediated directly within the brain and does not involve CB1 or CB2 receptor activation. Rather, a role for central TRPV1 receptors in mediating, at least partially (IL-6), the effects of increased FAAH substrate levels on TLR4-induced neuroinflammation was observed. Furthermore, despite the pronounced effects of increasing FAAH substrate levels on TLR4-induced neuroinflammation, this was not associated with a change in sickness behaviour, but rather tended to attenuate anhedonic-like behaviour. Overall these findings demonstrate an important role for FAAH substrates within the brain in the modulation of TLR4-induced inflammatory responses which may have implications in the treatment of neuroinflammatory disorders.
It is well known that TLR4-induced inflammation is associated with behavioural alterations including fever, hypolocomotion, altered appetite, anxiety and anhedonia. The current data demonstrate that while PF3845 potently attenuates TLR4-induced cytokines in the brain, this does not alter the associated sickness behaviour (hypolocomotion, fever, reduced body weight and food intake). Similarly, recent data have demonstrated that systemic administration of PF3845 does not alter LPS-induced hypothermia in mice, although effects of FAAH inhibition on other sickness-related behaviours have not been reported prior to this study.
Despite this, the data suggest that FAAH inhibition may modulate immune-mediated anhedonia, a core symptom of psychiatric disorders such as depression. A recent study has demonstrated that OEA, but not PEA, attenuates LPS-induced anhedonia, an effect associated with attenuation of cytokine and inflammatory mediators in the brain. Thus, it remains to be determined if one or a combination of the FAAH substrates enhanced following administration of PF3845 is responsible for the anti-anhedonic effects observed here-in, or modulates other immune-related behavioural and physiological responses.
Furthermore, administration of the peripherally restricted FAAH inhibitor URB937 increased FAAH substrate levels peripherally, with slight increases in OEA and PEA, but not AEA, levels in the brain; this treatment regime did not alter TLR4-induced increases in the expression of pro-inflammatory
cytokines. These data suggest that either high levels of FAAH substrates in the brain are required to modulate TLR4-induced neuroinflammatory responses or alternatively, that the increase in levels of AEA within the brain, rather than OEA or PEA, is primarily responsible for mediating the effects on TLR-induced neuroinflammatory responses. Thus, taken together the data indicate that FAAH substrates act to modulate TLR4-, in addition to TLR3-, induced neuroinflammatory responses directly within the brain, rather than via modulation of peripheral immune responses. AEA has been proposed to mediate some of its anti-inflammatory activity by increasing glial production of the anti-inflammatory cytokine IL-10.
FAAH substrates may act to down-regulate or delay glial activation under TLR4-induced neuroinflammatory conditions.
The current findings demonstrate that FAAH substrate-mediated attenuation of TLR4-induced increases in IL-1b and IL-6, is likely not mediated by central CB1 or CB2 receptors, given the lack of effect of i.c.v. administration of selective antagonists for these receptors on the immunosuppressive effect of PF3845. It should be noted that only in the presence of central CB1 or CB2 antagonism did PF3845 attenuate LPS-induced TNFa expression in this study.
However, AEA and FAAH substrates are known to also mediate effects via alternative receptors including the PPARs, TRPV1 and GPR55. For example, AEA-induced activation of PPARG has been shown to inhibit IL-2 release and PPARG was shown to mediate, at least in part, the effect of the putative AEA reuptake inhibitor AM404, on increases in plasma TNFa, induced following systemic TLR4 activation. However, the present findings demonstrated that blockade of either PPARA or PPARG, or the newly classified cannabinoid receptor GPR55, directly within the brain, does not alter FAAH substrate-mediated attenuation of IL-1b or IL-6 following LPS. In comparison, TRPV1 antagonism prevented the FAAH substrate-mediated attenuation of TLR4-induced increases in frontal cortical expression of IL-6, highlighting an important role for central TRPV1 in mediating, at least some of the effects, of FAAH substrates on TLR4-induced neuroinflammation. Several lines of evidence indicate that TRPV1 activation exerts anti-inflammatory effects under a variety of experimental conditions. However, to our knowledge this is the first study to report effects of TRPV1 in the modulation of TLR4-induced neuroinflammatory responses.
It should be noted that in addition to AEA, OEA is a potent TRPV1 agonists/desensitizer. Furthermore, several studies have demonstrated that FAAH inhibition can lead to indirect activation/desensitization of TRPV1, and thus shunting of the effect of AEA and other FAAH substrates onto other receptor targets which in turn mediate analgesic and anti-inflammatory effects. The current data demonstrate that although FAAH inhibition attenuates early neuroinflammatory responses to TLR4 activation, an effect partially mediated by TRPV1, this is not accompanied by alterations in sickness behaviour or anhedonia. Thus, while one or a combination of FAAH substrates may be responsible for the TRPV1-mediated decrease in LPS-induced IL-6 following PF3845, multiple receptors, mechanisms and circuitries are involved in mediating the behavioural responses.
Evaluating the possible receptor mechanisms revealed that the effects are independent of central cannabinoid receptors (CB1, CB2, and GPR55) or PPARs (PPARA/G) but rather demonstrate for the first time a role for central TRPV1 in partially mediating FAAH substrate-mediated modulation of TLR4-induced neuroinflammation.
In my opinion FAAH inhibitors not only reduce anhedonia and depression, but also sickness behavior even if to a lesser degree. I also think that contrary to the article FAAH works peripherally in my case.

It may be particularly interesting that Berberine [500 mg – pills] definitely works in my case even if not to the extent as saffron or MACA. This was rather unexpected, but later I found a possible explanation why this could be so. I am going to discuss this in my upcoming post.


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Re: FAAH Inhibitors
« Reply #9 on: April 13, 2021, 02:55:36 PM »
I think I have good experience with two of the things you posted :)

Saffron and Cordyceps and Maca. Thank you for bringing this clue to me.

I take it in a supplement combined with other well known things (Fenugreek, Citrullin, Ginseng, Zinc, tribulus, Selenium, Histidin).
I'll report more on this sometime later.

I remember in another thread Quantum posted that he does not want to take things which boost libido, worried that it might end up giving him POIS, but I think this might not actually be a problem.
« Last Edit: April 13, 2021, 03:10:47 PM by berlin1984 »
My Protocol with adaoptogens, neurotransmitter precursors, energy production supplements helps with 80% of the symptoms with intercourse, 50% with masturbation.


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Re: FAAH Inhibitors
« Reply #10 on: April 15, 2021, 09:48:52 AM »
I think I have good experience with two of the things you posted :)

Saffron and Cordyceps and Maca. Thank you for bringing this clue to me.

I take it in a supplement combined with other well known things (Fenugreek, Citrullin, Ginseng, Zinc, tribulus, Selenium, Histidin).
I'll report more on this sometime later.

I remember in another thread Quantum posted that he does not want to take things which boost libido, worried that it might end up giving him POIS, but I think this might not actually be a problem.

I was also checking out your posts just the other day and I think the same even if we have slight differences. I bought a lot of stuff in the previous months (amongst them are Rhodiola rosea, fenugreek, citrulline malate and melatonin), but I didn't have the time to test out many things as I had the coronavirus for weeks and only used stuff that I had known to work. However I still got some results that may be of interest.

I haven't tested Rhodiola rosea (goldenseal) yet, but it contains berberine and Berberine pills definitely work for me even when used as an only supplement. The one I use have 500 mg berberis root extract standardized on 2 % berberine which is 10 mg per pill. The recommended daily dosage is one pill, but I used 3 pills in conjunction with an O without problems, although I don't know about the long term effects. I used it alone taking it one hour before and after O and also one before I went to sleep. Its overall effectiveness is not that great as of saffron or MACA, but nevertheless it works. It seems especially good in reducing red eye symptom. It could generally stop POIS to become systemic, but I still developed some chest pain. I could take berberine safely alongside saffron and MACA.
I was rather surprised as I expected it to enhance POIS as a PPARG agonist. Of course I haven't confirmed anything yet, so it could be my mistake to think so, but I also found out later that it actually inhibits FAAH, although indirectly through the stimulation of IL-12 release.
I can only encourage anyone to read this article by the way as it is about autoimmune diseases and looks to be highly interesting in relation to our case.
According to the knowledge available up to now, within the complexity of the neuroimmunology, it is possible to identify two major neuroendocrine functional systems involved in the psychoneuroendocrine regulation of the immune system, consisting of the brain opioid system-pituitary axis and the brain cannabinergic system-pineal axis, respectively provided by an immunosuppressive and an immunostimulatory role.
In contrast to the mu-opioid agonists, which inhibit IL-2 and IL-12 secretions and stimulate IL-10 release, CBD has been proven to stimulate IL-12 and IL-2 secretions and to inhibit that of IL-10, by improving the antitumor immunity, which is stimulated by IL-2 and IL-12, and inhibited by IL-10 and TGF-beta.
IL-2 deficiency and IL-6 high levels may be treated by MLT, while on the other side IL-12 deficiency and IL-10 enhanced secretion may be treated by CBD.
As far as the autoimmunity is concerned, the autoimmune disease-related enhanced production of IL-17 may be controlled by the cannabinoid agonists, including the endogenous ones, THC, and CBD itself, because of its inhibitory action on FAAH activity, even though it is not a direct cannabinoid agonist. Then, THC would be more effective in the treatment of autoimmune diseases, since autoimmunity-related chronic inflammation would be mainly depend on IL-17 abnormal secretion, which is inhibited by THC, whereas CBD could be particularly appropriate in cancer cure by counteracting IL-10-dependent suppression of the antitumor immunity and stimulating IL-12-dependent anticancer immunity. The secretion of IL-12 has been proven to be also stimulated by berberine. Then, the immunomodulating properties of CBD could be further enhanced by a concomitant administration of the pineal hormone MLT, because of its ability to stimulate IL-2 secretion from TH1 lymphocytes, or its direct cytotoxic effects against most cancer cell lines.
On the other hand IL-2 may either enhance or inhibit the autoimmune processes, since it may either activate the macrophage system with a following enhanced production of inflammatory cytokines, namely IL-6 itself, or stimulate T reg system in the presence of high concentrations of TGF-beta.
IL-12 may either stimulate autoimmunity-related inflammatory response by promoting TH1 differentiation and a consequent enhanced IL-2 release, or inhibit TH17 functions, with a consequent diminished production of IL-17, which has appeared to be one of the most important cytokines in determining the autoimmune reactions. Finally, the immunosuppressive effects of mu-opioid agonists, including morphine, consisting of inhibition of IL-2 and stimulation of IL-10 secretion, could be potentially therapeutic in the autoimmune diseases, but the potential stimulatory effect of mu-opioid agonists on IL-17 secretion could verify the benefit due to their inhibition on IL-2 and stimulation on IL-10.
At present, it becomes possible to interpret cancer cure as a simple reestablishment of the functions of cytokine network on the status of health, consisting of a perfect equilibrium between immunostimulatory and immunosuppressive cytokines, since a prevalence of immunostimulatory cytokines may allow autoimmune pathologies, whereas an exaggerated production of immunosuppressive cytokines may predispose to cancer development.
Unfortunately, despite the great number of experimental studies confirming the immunomodulating properties of some neurohormones or neuroactive molecules, namely MLT, CBD, THC, and mu-opioid antagonists, very few clinical studies have been performed up to now to evaluate the real effects of their possible combinations as a neuroimmune approach in the cure of systemic diseases, including cancer and autoimmune diseases, in an attempt to correct cancer and autoimmunity-related alterations in cytokine secretions by acting on the neuroendocrine regulation of cytokine network itself, instead of a direct artificial action on the immune effects of cytokines, as in the immunotherapy with monoclonal antibodies.

It is also true that saffron itself actually down-regulates IL-12, but it is still a FAAH inhibitor nevertheless.

I also had positive experiences with Tribulus terrestris, although not as much as with MACA. As I indicated earlier this could be due to the different packaging (pill vs capsule). I found a site where I can buy some empty capsules and I also plan to test berberine in a capsule form. Tribulus terrestris and MACA both enhance testosterone, but I am not sure about its role anymore so I still need to test this further.

This may explain why zinc works, although I have special problems with it. I haven't tested it much, so I don't really know how it affects my POIS.
NAPE-PLD is an enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE). This is a major part of the process that converts ordinary lipids into chemical signals like anandamide (AEA) and oleoylethanolamine (OEA).
NAPE-PLD was found to have no homology to the known phospholipase D genes, but can be classed by homology to fall into the zinc metallohydrolase family of the beta-lactamase fold.
...leading the authors to propose that activity should be correlated with zinc content.
NAPE-PLD knockout mice have been reported to have wild-type levels or very reduced levels of anandamide.
Bile acids bind with high affinity to selective pockets in this cavity, enhancing dimer assembly and enabling catalysis. NAPE-PLD facilitates crosstalk between bile acid signals and lipid amide signals.

I don't have any problems with selenium and I also take it from time to time, but I haven't specifically tested it against POIS. A few years ago I bought a selenium supplement and if I remember well I felt a bit better while taking it, but it is certainly not very potent, otherwise I would have realized it at the time.

I also used a Ginseng supplement a few years ago and it also had a weak positive effect, but I stopped using it as it was nothing major and I needed the money for other things. I will retest it later, but it has a low priority on my list.

I also found another tea that works especially well. The herb is called lungwort (Pulmonariae officinalis). It may not be available everywhere, but it is rather cheap. It also contains kaempferol, quercetin, apigenin and rosmarinic acid etc, so it is filled with the good stuff.
When I first tried lungwort I even had a weak-moderate "regular" chest pain, but it appeared after an O, so it wasn't a post-covid symptom. I ate a lot of cakes with walnuts and it probably contributed too. So it turns out that lungwort works really well. I drank about 1 liter of the tea and after an hour my chest pain was greatly reduced. The concurrent depression was also blown out of my mind and I felt really great generally. After a few hours the chest pain reintensified somewhat which shows how perpetual POIS is.
The only side effect was a severe non-burning flatulence. This can be inconvenient, but still better than the other symptoms. Maybe I should try to use some simeticon in conjunction as it also helped somewhat if I remember well. I don't regularly use saffron, but its effectiveness also became weaker after several use, however this side effect was also reduced. Still I don't think it will lose its effectiveness completely as MACA capsules still work even after half a year.
Brantner and Karting, based on thin layer chromatography (TLC) identification, reported on the presence of quercetin and kaempferol glycosides. A fingerprint of methanol extract of P. officinalis obtained using micro-two-dimensional TLC, indicated the presence of chlorogenic acid, myricetin, acacetin, glycosides of apigenin, quercetin (rutin and hyperoside), hesperetin (hesperidin), and naringenin (naringin). Furthermore, based on HPLC analysis, Neagu et al. reported that rosmarinic acid was the main constituent of both aqueous and ethanolic extracts obtained from P. officinalis, moreover small amounts of rutin, hyperoside, chlorogenic, and caffeic acids were also detected. Our research revealed that P. officinalis extract contains yunnaneic acid B—a unique molecule that has been isolated so far only from Salvia yunnanensis, and also confirmed the presence of large amounts of rosmarinic acid.

I read through the Physalis thread and I ought to try that too. If anyone checks the first link Muon provided in his comment you can see that besides other compounds Physalis contains rutin, myricetin, quercetin and kaempferol.

Although I had a positive surprise with Berberine I had an unpleasant one with Kudzu.
Kudzu [500 mg per capsule] is marketed as a supplement to help in the treatment of nicotinic and alcoholic withdrawal symptoms. Research points out that this effect is mainly due to the isoflavones it contains, namely daidzin and daidzein. It also contains genistein in a smaller amount. As daidzein and genistein are FAAH inhibitors I had high hopes for it, however it turned out to be in vain.
Actually I am not really sure what Kudzu does as it is rather elusive. Two times out of five it gave me a sharp headache. One of this occasion was when I took two capsules and nothing else. The first time I took it with MACA it gave me acute POIS, but at an other time almost nothing happened. It didn't do anything to depression even when I took two capsules. I think Kudzu generally enhances my POIS (some burning pain), but it doesn't do this very apparently. I will have to try some other supplements containing daidzein and/or genistein to shed some light on the matter.
Based on the data obtained thus far, we propose that the antidipsotropic (antialcohol abuse)  isoflavones suppress ethanol intake by modulating activity of the central reward pathways through inhibiting the catabolism of monoamine neurotransmitters, such as serotonin or dopamine.

Some other teas I tried in the meanwhile:
Rosemary tea (one liter) had mixed effects, but mainly beneficial.
I found a site that sells pharmaceutical quality rosmarinic acid oil, but I am currently low on funds.
Nevertheless I need to test it as lemonbalm (Melissa officinalis) and lungwort (Pulmonariae officinalis) also contains rosmarinic acid in somewhat greater amounts.
Sage tea (one liter) had mixed effects, but mainly detrimental in regard of POIS.
Sennae tea [1 deciliter!] is quite dangerous. First I only drank 1 deciliter and soon my stomach was rumbling which is usually not a good sign so I didn't drink any more. I think this is the only reason I avoided a severe diarrhea. Besides this it gave me really smelly farts in the next 12 hours. However in my opinion it didn't actually do anything to POIS. So unless someone has a really-really severe constipation I wouldn't recommend its usage and even then one should be careful with it.
Hibiscus sabdariffa (roselle) tea (one liter) didn't seem to do much in short term although I think it caused some bowel pain later. It was one of the first days of my covid-19 infection when I tried this so I will have to test it again of course. By the way Hibiscus down-regulates PPARG activity so it is important to know if it does anything interesting. It is rather strange how it helps diabetics even though they have an already down-regulated PPARG.
Hibiscus sabdariffa with worldwide distribution is a powerhouse of phytochemicals viz. polyphenolics, especially anthocyanins. The nutritional abundance imparts it antioxidant, hypocholesterolaemic, antiobesity, hypotensive, antidiabetic, immunomodulatory, anticancer, hepatoprotective, antimicrobial, renoprotective, diuretic and anti-urolithiatic properties.
Oral administration of the extract reduced fat tissue accumulation, diminished body weight gain and normalized the glycaemic index as well as reduced dyslipidemia. Also, the extract treatment attenuated liver steatosis, downregulated sterol regulatory element-binding transcription factor 1 (SREBP-1c) and peroxisome proliferator-activated receptor-gamma (PPARG), blocked the increase of IL-1, TNF- mRNA and lipoperoxidation and increased catalase mRNA.
When combined with chrysanthemum, butterfly pea and mulberry extract, it exerted additive intestinal maltase inhibition. On the other hand, its combination with chrysanthemum and mulberry caused synergistic inhibition of pancreatic -amylase.

It may still turn out that FAAH inhibition only contributes to the reduction of POIS inflammation, but is not a requirement for it. I found a great article about the targets of some of the best working compounds and one can see clear parallelisms.
Kaempferol in itself is a real all-rounder and has many common traits with quercetin.
Kaempferol inhibits COX-1, COX-2, LOX, agonist of PPARG, Nrf2, downregulates NF-kB, modest inhibitor of FAAH and it also has anti-cholinesterase activity and lowers amyloid-B formation.
Although this table is very informative it is not complete as both apigenin and quercetin are also FAAH inhibitors.
Besides the well known factors the agonism of Nrf-2 also seems interesting as it is indicated in both inflammation and COVID-19 pathogenesis. However curcumin and sulforaphane are also Nfr2 agonists and they still don't have a major effect on my POIS. Maybe I should combine them and see what they do.
It could be that kaempferol, quercetin and apigenin works so well because they do all of these things in conjunction. The beneficial compounds probably have a cumulative effect, but synergism can't be ruled out which could really enhance the overall effect. So even though lime (Tilia) tea contains kaempferol and quercetin, it may not be enough to make it really potent.  Lungwort contains quercetin, kaempferol, apigenin, rosmarinic acid and even more which could make a real difference. The same may be true for saffron.
PPARG modulation still seems to be the only connection amongst the compounds that enhance (deteriorate) my symptoms. For one this is problematic as they can conceal and antagonise the positive effects and the official literature is also somewhat contradictory regarding some of the compounds. Probably this is the reason why rosemary is not clearly beneficial and this could be the case with Kudzu if Genistein turns out to work.

The tables detail the targets of some flavanoids amd terpenoids of interest.


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Re: FAAH Inhibitors
« Reply #11 on: April 15, 2021, 09:59:12 AM »


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Re: FAAH Inhibitors
« Reply #12 on: April 15, 2021, 03:54:23 PM »
Quercetin Phytosome (Absorption)

Thanks for the information! I plan to try some quercetin capsules, but it is not on top of my priority list. The product you recommend could be really good. It is true that a higher peak concentration would not only make the effects stronger, but it would also result in a slower concentration drop and a longer effect which is desireable as my symptoms never stop. I will keep this in mind if I can gather the funds.