Post Orgasmic Illness Syndrome (P.O.I.S.)

General Category => POIS Research => Topic started by: Progecitor on March 01, 2021, 03:31:09 PM

Title: FAAH Inhibitors
Post by: Progecitor on March 01, 2021, 03:31:09 PM
Warning! This theory has been mostly disproved experimentally. Bore yourself at your own risk. Saffron and maca are effective though, so be sure to try them! Besides CBD oil is really beneficial for some and FAAH inhibition could be the key to that.

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

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.
Title: Re: FAAH Inhibitors
Post by: Iwillbeatthis 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....
Title: Re: FAAH Inhibitors
Post by: berlin1984 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?!)
Title: Re: FAAH Inhibitors
Post by: Progecitor 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.
Title: Re: FAAH Inhibitors
Post by: Progecitor 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?
Title: Re: FAAH Inhibitors
Post by: Journey 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
Title: Re: FAAH Inhibitors
Post by: Progecitor 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.
Title: Re: FAAH Inhibitors
Post by: Progecitor 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.
Title: Re: FAAH Inhibitors
Post by: Progecitor 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.
Title: Re: FAAH Inhibitors
Post by: berlin1984 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.
Title: Re: FAAH Inhibitors
Post by: Progecitor 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.


Title: Re: FAAH Inhibitors
Post by: Muon on April 15, 2021, 09:59:12 AM
Quercetin Phytosome ( (Absorption (
Title: Re: FAAH Inhibitors
Post by: Progecitor 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.
Title: Re: FAAH Inhibitors
Post by: Progecitor on April 21, 2021, 01:16:07 AM
The endocannabinoid (eCB) system is an important regulatory system of the central nervous system that regulates neurotransmission and synaptic plasticity and plays an important role in emotional and social responses and cognitive function.
CB1R activation is important for cognition and memory and modulates other physiological activities by regulating neurohormone levels and signal transduction. CB2R, which mainly has an immunomodulatory role in the body, is distributed in peripheral immune organs or tissues such as the spleen margin and thymus.
CB1R plays an acute/short-term regulation of the growth cone signal at the neurite tip and has a long-term effect on neural gene expression that affect neuronal wiring and overall connectivity. Activated postsynaptic neurons release eCBs into the synaptic cleft; these eCBs serve as retrograde messengers by acting on presynaptic CB1R and inhibit neurotransmission by one of two mechanisms: by blocking calcium influx in the case of glutamate, gammaaminobutyric acid (GABA), monoamine, and acetylcholine; and by targeting cyclic (c)AMP-protein kinase A signaling associated with long-term depression (LTD) through inhibition of adenylate cyclase-mediated control of cAMP levels. These processes in turn affect the activation of synapses and the transmission of excitatory and inhibitory signals, which are closely related to synaptic plasticity. After entering the cell, eCBs are transported to their target by eCB intracellular transporters such as FAAH-1 cannabinoid transporter, fatty acid-binding protein, and heat shock protein 70, among others. In addition, peroxisome proliferator-activated receptors (PPARs) on the nuclear membrane belonging to the ligand-activated nuclear hormone receptor family can bind eCBs, resulting in conformational changes in the receptor that ultimately lead to repression of eCB-related genes and increased production of intracellular reactive oxygen species such as O2?.
Plasma and cerebrospinal fluid AEA levels are higher in patients with schizophrenia than in normal control.
However, other studies have arrived at the opposite conclusion: one study suggested that eCBs can be used to treat schizophrenia by alleviating white matter deficits in glial cells as well as damage resulting from glutamate toxicity.
Circulating plasma levels of eCBs are reduced in patients with mild depression and chronic post-traumatic stress syndrome.
Hyperactivation of the hypothalamic–pituitary–adrenal (HPA)-axis has been implicated in the pathophysiology of depression. Blockers of FAAH and TRPV1 that increase AEA levels were shown to normalize HPA axis function and improve depression symptoms in Wistar rat.
eCBs are an effective auxiliary treatment for epilepsy.
eCB system is associated with Fragile X Syndrome and can be a promising therapeutic target.
Generally known that the most famous explanation for Alzheimer’s disease is the dopamine hypothesis. A recent study reported an interaction between dopamine and eCBs.
ECB ligands are derived from polyunsaturated fatty acids (PUFAs) in neuronal cell membranes and act on presynaptic membrane receptors to inhibit neurotransmitter release from presynaptic neurons, thereby modulating synaptic plasticity.
The eCB system may be one of the hubs for the association of PUFA metabolism with neuronal development. Recent studies have revealed that defects in n-3 PUFAs inhibit eCB-associated synaptic plasticity in vivo.
At the same time, the deficiency of n-3 PUFAs also decreased the synaptic regulation function of CB1R in mice.

It is suggested that the lack of n-3 PUFAs diet may lead to synaptic plasticity damage and learning and memory impairment in neurons, which may be due to the decrease in the inhibitory effect of the eCB system on neurotransmitter release.
Some population experiments showed that the decrease of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and AA was related to cognitive impairment, which affected social function.
When BTBR mice—which are frequently used as an ASD model—were given selective FAAH inhibitor to increase the activity of AEA, social deficits associated with ASD were abolished.
Down regulation of PPAR and GRP55 has also been reported in VPA rats. Although it is unclear how this relates to social behavior, recent data suggest that activation of hippocampal PPAR can improve cognitive performance.
Therefore, the down regulation of PPAR may lead to decreased cognitive ability and impaired social behavioral responses in ASD.
Glutamate excitotoxicity and inflammation are thought to be involved in the development of ASD, and PEA has been shown to simultaneously prevent glutamate toxicity and inhibit inflammatory responses.

My relationship to sex is like cocaine, although I haven’t tried that.
One possible mechanism of this association was elucidated in studies that found that FAAH mutant genotype exhibit increased reward-related ventral striatal reactivity in comparison to control subjects.
Given the evidence that the FAAH gene plays a role in modulating subjective mood as well as addiction pathways, we hypothesized that the FAAH variant is associated with alterations in subjective effects produced by cocaine in the laboratory.
It is generally agreed that the initial rewarding effects of many drugs are an elevation in mood and affect. In Pro129Thr variant allele carriers, the observed overall increased subjective effects to drug administration ("Effect" and "High") may help explain why there has been an increased risk of addiction found in this population. Another possibility is that substance-induced dysphoria incites further substance use, leading subjects into a cyclic negative reinforcement model. In this cycle, the negative effects on mood (ie, "Sad") that accompany cocaine use drive users to seek out more substance as a coping mechanism to reduce this dysphoria. Such a process has been described in detail by Dr. George Koob, who hypothesized that chronic excessive DA release produces activation of dynorphin systems, which feedbacks to decrease DA release and mediate dysphoric states seen in cocaine addicts. In FAAH variant carriers, these negative mood states appear to intensify.

Marijuana and its major psychotropic component, THC, were found to stimulate appetite and increase body weight in wasting syndromes. Additionally, endocannabinoids have been involved in the control of energy balance and food intake and their effects have been described as mainly CB1–mediated, since they are antagonized by SR141716A.
They may also stimulate lipogenesis and fat accumulation. Therefore, endocannabinoids add to the list of the numerous neurotransmitters and neuropeptides involved in the physiological control of appetite and satiety. In particular, 2-AG has been described to stimulate feeding in a potent and dose-dependent manner, effect blocked in part by the action of SR141716A.
Interestingly, the neurohormone leptin, which is the main regulator of the hypothalamic orexigenic and anorectic signals, exerts a negative control on the AEA and 2-AG levels. Considering the role played by endocannabinoids in the intricate network that regulates feed control, the manipulation of their levels could offer useful approaches to the treatment of eating disorders as well as metabolic syndromes.
These effects have been linked to CB1 receptor activation, considering that CB1 is expressed in these prostate cancer cell lines as well as in the human prostate gland (at a level comparable with the CB1 expression in cerebellum) where it negatively regulates adenylyl cyclase activity.
The brain reward system constitutes another point of interest for 2-AG since it has demonstrated a remarkable capacity to attenuate the naloxone-precipitated withdrawal signs in morphine-dependent mice. This result is in agreement with the proposed upregulation of cannabinoid CB1 receptors in morphine dependence, and it supports the hypothesis that either accelerators of endocannabinoid synthesis or inhibitors of its degradation may have a therapeutic potential to treat opiate withdrawal symptoms. The profound changes that the ECS undergoes during the different phases of sensitization to morphine in rats provide a possible neurochemical basis for this cross-sensitization between opiates and cannabinoids. Moreover, 2-AG could play a role in alcohol addiction and in addictions to other drugs such as marijuana, nicotine, and cocaine by activation of the same or related reward pathways.
2-AG as well as anandamide could mediate opioid-independent stress-induced analgesia. Another aspect of interest is the presence of the CB1 receptor and both AEA and 2-AG in ocular tissues. Cannabinoids have shown capacity to reduce the ocular hypertension and, in particular, topical application of anandamide was shown to decrease the intraocular pressure in normotensive rabbits. Moreover, topical administration of 2-AG and noladin ether also decreased intraocular pressure in rabbits, reduction that has been attributed to the CB1 receptor. These effects could be of direct application in glaucoma, the disorder characterized by a pathological enhancement of the intraocular pressure. In this regard, the levels of 2-AG and N-palmitoylethanolamine have been found to be significantly decreased in the ciliary body in eyes from patients with glaucoma, further supporting the role of these endogenous compounds in the regulation of intraocular pressure.
Finally, the role of 2-AG in the immune system and in particular its effect on the motility of human natural killer cells should be noted, 2-AG induces the migration of KHYG-1 cells (a natural killer leukemia cell line) and human peripheral blood natural killer cells. This migration can be blocked by the presence of the CB2 antagonist SR144528, and interestingly, it does not occur in the case of AEA or THC. Accordingly, it has been suggested that 2-AG could contribute to the host-defense mechanism against infectious viruses and tumor cells.

An overexpression of MAGL could similarly lead to a kind of endocannabinoid depletion.

Thus, substitution of the glyceryl moiety by a thienylmethyl group as in CAY10402 abolishes MAGL activity while keeping a low FAAH inhibitory potency (IC50 = 10 ?M). Within this category fall a couple of old known compounds, N-(4-hydroxy-2-methylphenyl) arachidonamide (VDM11) and N4-(hydroxyphenyl) arachidonamide (AM404). Originally proposed as anandamide uptake inhibitors, they are also FAAH inhibitors. This work reveals that AM404 and its analogue VDM11 inhibited the metabolism of anandamide by rat brain FAAH equipotently (IC50 = 2.1 and 2.6 ?M, respectively) and to a lesser extent the degradation of 2-OG by cytosolic MAGL (IC50 = 21 and 20 ?M, respectively).

Indian mulberry may refer to Morinda citrifolia also called noni, beach mulberry, and cheese fruit. Morinda citrifolia (Noni) Fruit Juice Inhibits Endocannabinoid Degradation Enzymes.
Morinda citrifolia (noni) fruit juice has been shown to have a wide variety of potential health benefits in human clinical trials. It may also influence the endocannabinoid system of the body. Since the main ingredient of the product studied in these clinical trials was juice made from noni fruit puree from French Polynesia, it was evaluated for its ability to inhibit the two major endocannabinoid degradation enzymes in vitro. Noni fruit juice inhibited both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a concentration-dependent manner, suggesting that it may help maintain anandamide and 2-arachidonoylglycerol levels. Samples of the puree were also analyzed for the presence of characteristic phytochemical markers of authentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic acid and asperulosidic acid, all of which were present. Also present was scandoside, which is reported for the first time as being identified in noni fruit or its juice. Some of these compounds may contribute to the FAAH and MAGL inhibiting activity of noni juice. These results reveal another set of mechanisms by which noni juice possibly supports mental health, maintains joint health, relieves discomfort and modulates the immune system.

This can probably rule out 2-AG in my case.
N-3-methoxybenzyl-linoleamide is one of the most active FAAH inhibitors from the Maca plant and was studied to evaluate and characterize its FAAH and MAGL inhibitory activity using in vitro assays. The results demonstrate a time-dependent and mixed inhibition on FAAH, while no inhibitory effect was observed on MAGL. Maca is known to contain macamides (alkamides), alkaloids, isothiocyanates, polyunsaturated fatty acids (macaenes), sterols, glucosinolates, amino acids, minerals, and vitamins. Naturally occurring and synthetic alkamides have been found to possess in vitro neuroprotective effects in rat neuroblastoma cells and in animal models of stroke.

Cyanidin-3-O-glucoside, also known as kuromanin, is one of the most important anthocyanins in nature. The scope of this paper is to discuss the potential role of this anthocyanin as therapeutic agent to prevent or treat chronic diseases in which oxidative stress may be involved through a modulation of certain enzymes.
Cyanidin-3-O-glucoside inhibited MAO-A, TYR and FAAH enzymes whereas it could not inhibit AChE activity. IC50 values for these assays were 7.6??M, 18.1??M and 152.1??M, respectively. Additionally, cyanidin-3-O-glucoside was able to inhibit ?-GLU (IC50?=?479.8??M) and DPP-4 (IC50?=?125.1??M). Finally, the antioxidant activity of cyanidin-3-O-glucoside was confirmed by the xanthine/xanthine oxidase method, being more efficient than gallic acid as superoxide radical scavenger. In conclusion, cyanidin-3-O-glucoside has demonstrated to be a candidate as enzyme inhibitor with neuroprotective, antioxidant and antidiabetic potential.

Supplementary Table 3. on the last pages contains an extensive list of plants with FAAH inhibitory property.

I have rechecked the covid-19 article about arachidonic acid (AA) for some further information.
Subjects with obesity, hypertension, type 2 diabetes mellitus (DM) and coronary heart disease have low plasma concentrations of AA, whereas elderly have decreased activity of desaturases that results in low plasma levels of AA and low LXA4 levels. This may explain why these subjects have severe COVID-19 and are more prone to cytokine storm and resultant mortality.
This implies that there are two phases in the pathobiology of COVID-19, the first one is characterized by hyperinflammation that may happen in the beginning of COVID-19 and the second phase could result in immunosuppression with little or no change in the levels of pro-inflammatory cytokines as in sepsis.

FAAH is also over-activated in DM.
As the eCB system is also involved in diabetes mellitus, some medications like tropisetron and glibenclamide may be worthwhile to test if they become available.
The CB1 receptor is widely expressed in the central nervous system and peripheral tissues such as the liver and its activation increases the level of reactive oxygen species (ROS) and inflammatory mediators.
It has been shown that in the liver of hypertensive rats an increase in the activity of FAAH is related to inflammatory conditions as well as oxidative stress.
Diabetes caused a significant reduction of CB1 receptor protein levels in the liver of male rats in comparison with the control group. Treatment with tropisetron and glibenclamide for two weeks reversed these protein levels.
Diabetes was associated with a significant decrease (p < 0.001) in CB1 receptor and a significant increase (p < 0.001) in FAAH enzyme gene expression compared to the control group.
Moreover, structural protein degradation in the target tissues of insulin in diabetic subjects is fundamentally associated with a sudden weight loss.
Rahimian et al. reported that tropisetron-induced calcineurin inhibition, a pivotal enzyme in the inflammatory process, might underlie the alteration in CB1 receptor expression.
In contrast to our study, with a lower CB1 receptor expression, increased CB1 receptor levels have previously been reported in hepatic tissues and some other organs in streptozotocin-treated rats.
Down-regulation of the CB1 receptor is accompanied by an increased level of endocannabinoids, which contributed to oxidative stress, inflammatory status, and subsequently the activation of caspase3 and apoptosis.
In addition, it seems that an increase in endocannabinoid biosynthesis enhances the activity of the main enzymes degrading endocannabinoids such as FAAH which is probably due to the feedback mechanism in response to an increased level of the anandamide (AEA).
FAAH is a major degrading enzyme of the AEA which participates in controlling tissue injury, partly mediated through the activation of cannabinoid receptors by endocannabinoids.

Linoleic acid, a common component of dietary fat, and its metabolic derivative, arachidonic acid (AA), have both been associated with prostate tumor progression.

Guineensine is a natural benzodioxole-alkenyl-N-isobutylamide derivative isolated from Piper nigrum. As described by Nicolussia and coworkers guineensine is a new nanomolar inhibitor (EC50= 290 nM) of cellular uptake of the endocannabinoid anandamide, through a mechanism of action that doesn't involve inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL). Despite its ability to induce cannabimimetic effects in BALB/c mice, such as catalepsy, hypothermia and analgesia activity, it is not able to interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier, revealing an intriguing mechanism of action that should be better elucidated.

All major ECS components have been found in female and male reproductive systems, and eCB levels in tissues and body fluids hold promise as disease biomarkers. Of note, the presence of a high concentration of AEA in follicular fluid is indicative of mature follicles, and significant differences of AEA and PEA in serum, and of OEA in follicular fluid, have been recorded between infertile and fertile women. Furthermore, dysregulation of the ECS has been observed in polycystic ovary syndrome (PCOS) onset, as well as in altered human endometrial stromal cell decidualization.
An essential role for GPR55 activation in the Ca2+-dependent regulation of human sperm motility and capacitation has been proposed.

Inhaled anandamide has been shown to attenuate leukotriene D4-induced airway obstruction in guinea pigs. Mice lacking CB1, CB2, or both, and those treated with a CB receptor antagonist displayed exacerbated T-cell-mediated allergic skin inflammation. The inflammatory response was attenuated in animals lacking the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) and in those treated with CB receptor agonists. These observations suggest that anandamide release could serve as an inhibitory feedback mechanism restraining airway obstruction and inflammation in allergic asthma. We hypothesized that pulmonary anandamide concentration increases with experimental allergen exposure.
Title: Re: FAAH Inhibitors
Post by: Progecitor on April 22, 2021, 02:09:54 AM
Some thoughts on the Nrf2 inflammatory pathway. It may be involved in my case, but I don't think it is the root cause for me. However it may be important in other cases especially if both sulforaphane and curcumin prove effective.

The genes that are involved in the NF-kB signaling pathway were found to be upregulated, along with increased levels of cytokines and inflammatory markers, showcasing the involvement of this pathway in the hyperinflammatory response in patients with COVID-19. NF-kB (nuclear factor kB) is a family consisting of inducible transcription factors that regulate the genes involved in immune and inflammatory responses. These normally exist in the cytoplasm in a sequestered form by inhibitory proteins that include the IkB family and some other related proteins.
Nrf2 (nuclear factor erythroid 2 related factor-2) is a transcription factor that forms the genes coding for various enzymes that protect the cells from oxidative or electrophilic stress. It also transcriptionally represses inflammatory genes that regulate the inflammatory response. Normally, Nrf2 exists in bound form in the cytoplasm with its inhibitor, Keap1. When the cell is under stress, electrophile or ROS (reactive oxygen species) generation leads to dissociation of Nrf2-Keap1 complex and Nrf2 migrates into the nucleus to stimulate the transcription of a multitude of genes that are involved in redox homeostasis and anti-oxidant response. Biopsies in COVID-19 patients have revealed that genes associated with Nrf2 anti-oxidant response were suppressed in these patients. Also, in vitro experiments showcased that the Nrf2 inducible proteins expression was also downregulated that tells the suppression of this pathway in COVID-19 patients. A study on Nrf2 activator showed that it downregulated 36 genes that encode cytokines resulting in a decrease in the cytokine storm in COVID-19.
All the above studies point to the involvement of Nrf2 and NF-kB in the pathogenesis of COVID-19. Since one of the mechanisms of neurological complications is through immune injury by the cytokines, the involvement of these signaling pathways in these complications can be well attributed. A study on transgenic mice also revealed that when the Nrf2 pathway was activated, it suppressed oxidative stress and improved the cognitive function of mice. When the pathway was blocked, it resulted in oxidative injury and a decrease in the viability of neurons. As this pathway is reported to be downregulated in COVID-19 patients, this could be one of the possible causes of cognitive decline.

NF-kB Pathway and COVID-19
The NF-kB (nuclear factor k-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways which provide mechanisms for stimuli that link to inflammation. It influences the growth of axons and dendrites originating right from the earliest stages of neuron establishment. A lipopolysaccharide receptor complex is formed by toll-like receptors and the adaptor proteins present in the extracellular matrix. The signal pathway leads to activation of NF-kB. The blood–brain barrier prevents the entrance of immunogenic cells into the central nervous system. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-kB pathways. Besides neurons, NF-kB transcription factors are abundant in glial cells and cerebral blood vessels, and the diverse functions of NF-kB also regulate the inflammatory reaction around the neuronal environment. NF-kB transcription factors are abundant in the brain and exhibit diverse functions. The pathogenesis of COVID-19 is similar to earlier discovered viral disorders namely cytomegalovirus, MERS, and varicella. Similarly, COVID-19 can cause activation of the NF-kB pathway which ultimately may lead to stroke or neuropathy associated with thromboembolism in the brain. The heightened immune response specially, the cytokine storm is characterized by an elevation in IL-6, IL-10, IFN-g, and TNF-a in the granulocyte colony–stimulating factor. The genetic induction of innate and adaptive immunogenic cells is influenced by NF-kB. Deregulated activation leads to activated T-cells in association with autoimmune inflammation and inflammasome release. In a preclinical study, NF-kB influenced the regulation of various proinflammatory mediating chemicals. When inhibitors of NF-kB like parthenolide were administered, a reduced infection was seen. The NF-kB transcription is unmasked by the degradation of IkB which is phosphorylated by protein kinases activated by mitogens. The upregulated proinflammatory genes result in excessive cytokine and reactive oxygen species which cause cerebellar damage and neuropathogenic dysregulation associated with neurotransmitters.

Nrf-2 and COVID-19
Nrf2 belongs to the basic leucine transcription factor and influences oxidative stress by expressing antioxidant genes. Nrf2 remains situated in the cytoplasm wherein it binds with keap1, which is a known inhibitor of Nrf2. When reactive oxygen species emerge, the Keap1-Nrf2 complex gets dissociated and as a result, Nrf2 migrates towards the nucleus leading to stimulation of target genes eliciting an antioxidant action whose activation enforces protection from inflammation. Upregulation in expressing Phase 1 and 2 drug-metabolizing enzymes in addition to the mitochondrial pathways is also a characteristic of this pathway. The upregulated target genes include glutathione S-transferase, catalase, heme oxygenase 1, and superoxide dismutase. These protect neuron function from oxidative degradation. All primary factors including oxidative degradation, inflammatory upregulation, and dysfunctional mitochondria contribute to aging of brain which exposes patients at a risk of neurodegenerative diseases. Nrf2 can prove to be beneficial in case of COVID-19 infections due to its attractive efficacy against such pathologies. To eradicate stress induced by oxidative species, Nrf2 is released, stabilized, and translocated. Nrf2 acts as an on-off switch and produces endogenous antioxidative relief. Several kinases like phosphoinositol-3 kinase, protein kinases, and pancreas enriched kinase also act as regulators of Nrf2 activity. Mitogen-activated protein kinases are enzymes that contain protein kinases regulated extracellularly. They catalyze the phosphorylated reactions on the amino acid serine, threonine residues which reside right next to the proline amino acid. The mitogen-activated protein kinase pathway works in response to oxidative stress and has been implied in the induction of the Nrf2 pathway. The signals are mediated by the extracellular regulated kinase and mitogen activated kinases which culminate in upregulation of glutamate cysteine ligase modulatory subunit gene, influencing nuclear translocation of Nrf2. While Nrf2 and Keap1 are not directly targeted, the mitogen-activated kinases are directly involved in the translocation of Nrf2 into the nucleus.

Crosstalk Between NF-kB and Nrf2 Pathways
After the virus replicates inside the host, the innate immunogenic response causes activation of many inflammatory mediators namely macrophages and dendritic cells to fight against cytokines and reactive oxygen species. The reactive oxygen species and inflammatory cytokines damage erythrocytes releasing heme and free ion. Respiratory burst generates superoxide radicals and hydrogen peroxide which ultimately, cause oxidative stress. The cytokine storm is a consequence of the upregulated cytokine expression through the NF-kB pathway. This storm is responsible for severe damage to the tissue.
In a study that induced scratch injury in astrocytes, it was found that this injury caused upregulation of NF-kB activity that resulted in overexpression of IL-6, IL-1B, TNF-a, and MMP9 (matrix metallopeptidase 9-gelatinase that aggravates inflammation process). This overexpression was found to be more aggravated in Nrf2 knockout astrocytes than the wild-type resulting in more astrocyte death. In another experiment, Nrf2-deficient mice showed greater pro-inflammatory gene expression on TNF-a stimulation. NF-kB activation after LPS (lipopolysaccharide) activation was also found to be high in the lungs, MEFs (mouse embryonic fibroblasts), and peritoneal macrophages of Nrf2 deficient mice. These also showed higher IKK Kinase activity in response to TNF-a or LPS. These studies point to the possible interplay between Nrf2 and NF-kB. It is proposed that these pathways exert an inhibitory effect on each other at the transcription level. The crosstalk can be both ways-Nrf2 inhibition of NF-kB and vice versa.
Nrf2 produces a multitude of antioxidant and cytoprotective enzymes in response to oxidative stress. One of them, HO-1 (hemoxygenase-1), is involved in the metabolism of heme by acting as a catalyst in the cleavage of porphyrin ring in heme into carbon monoxide, Fe2+, and biliverdin that converts into bilirubin. A study showed that overexpression of HO-1 in the endothelial cells inhibited TNF-a-induced proinflammatory adhesion molecule expression (E-selectin and VCAM-1 (vascular cell adhesion protein 1)). This inhibition was found to be at mRNA level by interfering with the rate of transcription. This represents one way of the crosstalk that the Nrf2 pathway inhibits NF-kB pathway activation by increasing HO-1 expression, thus reducing the cytokine release. Oxidative stress also causes IKK (IkB kinase) activation that further phosphorylates IkB which is the inhibitor of NF-kB and causes polyubiquitination mediated proteasomal degradation that releases NF-kB. It migrates to the nucleus and leads to the transcription of inflammatory genes. Nrf2 pathway inhibits degradation of IkB-a that leads to its stabilization and inhibition of NF- kB-mediated transcription. Hence, the release of pro-inflammatory cytokines is inhibited.

NF-kB can also regulate Nrf2 mediated ARE (antioxidant response element) expression.
This strengthens the view that NF-kB activation suppresses the Nrf2 pathway in case of enhanced oxidative stress or cytokine storm.

Keap1, with which Nrf2 exists in bound form in the cytoplasm, has been found to negatively regulate IKKB. HSP90 (heat shock protein 90) is a chaperone protein that assists in protein folding. It has been observed that Keap1 prevents the binding of HSP90 to IKKB which is the trigger for its autophagic degradation. Also, Keap1 reduces IKKB phosphorylation by concealing those residues that bind with the phosphate groups. The result of this entire interaction is that IkB-a is stabilized because IKKB is not phosphorylated that, as a result, reduces NF-kB signaling.
Patients with pre-existing auto-immune disorder susceptibility are at grave risk for COVID-19. Due to the administration of immunosuppressant for mitigating the virus, the interest in auto-immunity is implied. The dysfunctional regulatory T cells have been regarded as the cause of many autoimmune disorders. When Nrf2 is systemically activated by Keap1 (Kelch-like ECH-associated protein 1), tissue inflammation is enhanced. On the other hand, its knockdown reduces T cell and cytokine production. Nrf2 induction can mitigate the regulatory T cell dysfunction and alleviate auto-immune disorders especially, in the case of COVID-19 where the latter is further stressed upon. NF-kB has a role in promoting inflammation in autoimmune attacks as well as mediating immunogenic tolerance. It promotes the formation of regulatory T cells and plays a role in deleting self-reacting T cells situated in the thymus. The NF-kB thus lies centrally in preserving immune homeostasis and prevention of autoimmunity caused in COVID-19.
COVID-19 is characterized by a cytokine storm due to the attack on the patient’s immune cells. The mainstay of treatment is the use of anti-viral agents. Immunomodulatory agents both synthetic and herbal can be pertinent in catering and resolving the serious effects of the attack of the virus. These immunomodulatory agents act in synergism with the pre-existing approaches and act as adjunctive therapy or prophylaxis. The Nrf2 and NF-kB pathway are involved in the development and progress of inflammatory pathology in COVID-19. Consequently, immunomodulators targeting the crosstalk between these key signaling pathways offer an innovative approach in tackling this deadly pandemic and present a ray of shine in tackling COVID-19 associated neurological complications.
Oxidative stress and inflammatory cytokine storm are key characteristics of the pathology concerning this deadly virus. Many studies discussed point the substantial body of evidence hinting at severe neurological complications in patients.
Crosstalk between both, NF-kB and Nrf2 signaling pathway lies at the center of neurological complications in COVID-19 patients. Immuno-modulators both synthetic and natural can be promising candidates in catering to the pathologies targeted in the aforementioned pathways. Immunomodulatory agents act in synergism with the pre-existing approaches and act as adjunctive therapy or prophylaxis and outstand existing approaches by specifically targeting the oxidative stress and consequently, eradicating and undermining the pathology leading to severe neurological disorders.

Check out figure 6!

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRPA1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
TRP channels are polymodal channels and most of the superfamily members can be activated by a multitude of stimuli. Several Nrf2-interacting nutrients are direct TRPA1 activators. These include: (i) allyl isothiocyanates (AITC: pungent components of mustard, horseradish, and wasabi), cinnamaldehyde from cinnamon, (iii) allicin, an organosulfur compound from garlic, (iv) green tea polyphenols, and (v) 3 glucosinolates from Sisymbrium officinale (isopropylisothiocyanate and 2-buthylisothiocyanate) or Moringa oleifera (4-[(a-l-rhamnosyloxy) benzyl] isothiocyanate). Sulforaphane, an AITC and the most potent natural Nrf2 activator, does not appear to interact with TRPA1. The plant polyphenol resveratrol may have an agonist or antagonist effect. An indirect agonist effect was found via the N-methyl-D-aspartate (NMDA) receptor in vivo. TRPA1 may serve as a downstream target of pro-nociceptive ion channels such as N-methyl-D-aspartate receptors.
Many TRPV1 agonists also interact with Nrf2 and/or TRPA1. TRPV1 is a sensor stimulated by several spices including capsaicin (red pepper), piperine (black pepper), gingerol, and zingerone (ginger), pungent compounds from onion and garlic, eugenol (clove), and camphor. TRPV1 is also activated by AITC, present in mustard, horseradish, and wasabi, and by resiniferatoxin, a toxin of tropical Euphorbia plants.
There is a substantial overlap of electrophilic ligands between TRPA1 and Nrf2. However, not all Nrf2-interacting nutrients are activators of TRPA1. For example, mustard oil does not interact with Nrf2, whereas sulforaphane does not interact with TRPA1 or TRPV1.

Check out Table1!
Paracetamol (acetaminophen) has TRPA1-independent antipyretic effects and TRPA1-dependent effects on pain. The electrophilic metabolites N-acetyl-p-benzoquinone imine (NAPQI, hepatotoxic metabolite) and p-benzoquinone, but not paracetamol itself, activate TRPA1. They also activate and sensitize TRPV1 by interacting with intracellular cysteines. NAPQI also directly activates Nrf2, and benzoquinone desensitizes TRPA1.
The physiological and toxicological responses of paracetamol form a continuum coordinated by the Wnt and Nrf2 pathways. Therapeutic doses produce reactive ROS and NAPQI in the cytoplasm but result in little permanent damage. At high doses, paracetamol can induce oxidative stress-mediated hepatotoxicity which is reduced by enhancing the Nrf2 pathway.
The oxidative stress senses TRPA1 and, to a lesser extent, TRPV1. The activated TRPs are prone to be hyper-activated by various natural stimuli. Foods can activate Nrf2 and desensitize TRPs.
Reducing ROS by Nrf2 will most likely reduce TRPA1 hyperreactivity, thereby reducing TRPA1 activation by exogenous or endogenous agents.

Even though epidemiological studies have suggested that children with low dietary intake of vitamins and C, E and other antioxidants have in general more symptoms, the results of the clinical studies have been largely disappointing. Interestingly, a recent study has even suggested that vitamin supplements may increase the oxidant stress. In this study, the investigators have hypothesized that the intake of antioxidant vitamins would augment the beneficial effects of exercise in patients with type 2 diabetes. In contrast to their expectations, the results have shown that daily supplementation with vitamin C and vitamin A for 4 weeks not only failed to improve the insulin responsiveness but also decreased the expression of ROS-sensitive transcriptional regulators, molecular mediators of ROS defense (SOD 1 and 2, glutathione peroxidase). Thus, antioxidant supplement seems to have blocked endogenous defenses rather than counteract the oxidant stress. This emphasizes that exogeneous antioxidants need to block the oxidant pathways without suppressing the endogenous antioxidant mechanisms.
The Nrf2 pathway is a negative regulator of inflammation according to the hierarchical oxidative stress model. Sulforaphane is a potent Nrf2 agonist, which is found in high amounts in broccoli.
Studies using human bronchial epithelial cells confirm that sulforaphane is effective in suppressing the proinflammatory effects of diesel exhaust particles. It effectively upregulates GSTM1 and blocks interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor (GMCSF), IL-1B production in the bronchial epithelial cells.
Quercetin is a flavonoid molecule found in a variety of foods especially in apples and has antioxidant and anti-inflammatory properties. Quercetin was shown to inhibit proinflammatory cytokines and NO production through MAP kinases and NF-kB pathway in lipopolysaccharide-stimulated cells.
Dietary intake of the soy isoflavone genistein was associated with reduced allergic respiratory symptoms.
In animal models, genistein blocks allergen-induced airway inflammation in ex vivo allergen-challenged guinea-pig bronchi and lung specimens. Intratracheal instillation of genistein was shown to reduce leukotriene and histamine levels. In support of these studies, asthma patients with high dietary genistein consumption had less severe airflow obstruction than those who consume little or no genistein.
a-Lipoic acid is a nonenzymatic antioxidant and is present in various foods and oral supplements. In an animal model, a-lipoic acid treatment was associated with reduced airway hyperresponsiveness, lower eosinophil counts, and IL-4 and IL-5 concentrations in BAL, improved pathology of the lungs, and lower intracellular ROS and NF-kB DNA-binding activity. Recently, Metha et al reported that choline and a-lipoic acid treatment reduces ROS production and isoprostanes in BAL fluid and thus suppresses oxidative stress.
Another food derivative, epigallocatechin 3 gallate, a component of polyphenols derived from green tea, was shown to be a potent inhibitor of IL-1B-induced MUC5AC gene expression and MUC5AC secretion and has antioxidant activity.

Prospective natural compounds in the management of the coronavirus infection.
Check out Table 1!

Other Nrf2 modulator compounds.
Check out Table 3!

This could give some ideas of some potentially effective combinations. Check the tables at the link!
The heartburn the patient (author) experienced is probably in line with mine.
For those who have a positive experience with sulforaphane, black pepper, curcumin and paracetamol the Nrf2 pathway should be seriously considered!
Antioxidants have been proposed as being effective in controlling COVID-19 symptoms. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most effective antioxidant mechanism. TRPA1 (transient receptor potential ankyrin 1) is highly sensitive to oxidative stress and induces several COVID-19 symptoms. TRPA1 and TRPV1 (transient receptor potential vanillin 1) are potential candidates for COVID-19 symptoms.
Nutrients with various Nrf2 and TRPA1/TRPV1 agonist activity were used: broccoli seeds (potent Nrf2 agonist and mild TRPA1 agonist), berberine (Nrf2 only), black pepper, curcumin, ginger, green tea, resveratrol, Zinc (potent TRPA1 activity and variable Nrf2 agonist) and red pepper (potent TRPV1 agonist).
Berberine and Zinc were not effective. All other nutrients except resveratrol were rapidly effective (1-10 minutes). The effect of green tea, curcumin + black pepper, ginger, resveratrol or red pepper disappeared in 1 to 4 hours. Broccoli had a longer duration of action (5-7 hours). The duration of the of the effect increased to around 10 hours when low doses of curcumin + black pepper or resveratrol were added to broccoli. Paracetamol low dose (its metabolite N-acetyl-p-benzoquinone imine is a TRPA1/TRPV1 agonist) increases the duration of action of combinations to over 14 hours.

Differences in COVID-19 death rates among countries may in part associated with Nrf2 and Nrf2-interacting nutrients like fermented vegetables could reduce COVID-19 severity.
TRPA1, an excitatory ion channel, plays a pivotal role in augmenting sensory or vagal nerve discharges, evoking several COVID-19 symptoms.
It is highly sensitive to oxidative stress. In COVID-19, rapid desensitization of TRPA1
and/or TRPV1 may reduce symptom severity.
It is difficult to deliver sulforaphane in an enriched and stable form for human consumption, thus glucoraphanin, the precursor of sulforaphane, is administered orally with myrosinase, the enzyme that transforms glucoraphanin into sulforaphane.
All nutrients tested have a variable Nfr2 agonist activity. Although the specificity of the different agonists is not clearcut it can be considered that curcuma and black pepper, ginger, green tea, quercetin and the plant polyphenol resveratrol are all TRPA1 agonists, whereas berberine does not appear to have such an effect. Capsaicin from red pepper is the agonist of TRPV1 but it also has some TRPA1 activity. Zinc acts on Nrf2 and TRPA1.

The electrophilic metabolites N-acetyl-pbenzoquinone imine (NAPQI, hepatotoxic metabolite) and p-benzoquinone, but not paracetamol itself, activate TRPA1 and TRPV1. NAPQI also directly activates Nrf2, and benzoquinone desensitizes TRPA1.
When the patient initially took capsules containing curcumin and black pepper, he experienced some gastro-esophageal discomfort and heartburn (VAS 2-3/10 for pain). However, when red pepper was associated with paracetamol heartburn increased (VAS 6) and required lansoprazole 30 mg. This discomfort lasted for around one to 2 hours.

Berberine (BBR) is a natural isoquinoline alkaloid with very impressive health benefits. It is one of the most effective natural supplements available. BBR supplemented either before or after methotrexate (MTX) significantly ameliorated body weight, liver function markers, TNF-a, lipid peroxidation, NO and caspase-3. BBR increased serum albumin and liver antioxidant defenses in MTX-induced rats. Histological and immunohistochemical examination showed improved histological structure and decreased expression of Bax in liver of MTX-induced rats treated with BBR. In addition, BBR up-regulated Nrf2, HO-1 and PPARG expression in the liver of MTX-induced rats. In conclusion, BBR attenuated MTX-induced oxidative stress and apoptosis, possibly through up-regulating Nrf2/HO-1 pathway and PPARG. Therefore, BBR can protect against MTX-induced liver injury.

Title: Re: FAAH Inhibitors
Post by: Progecitor on April 23, 2021, 01:43:55 PM
I think that PPARG is the single unifying factor that must be the root cause for almost all if not all of the POIS cases. Although most of the FAAH inhibitors work in my case, however the only common link between the enhancers is that they modulate PPARG. Other POIS cases also have a connection to PPARG most of the time. Even researchers confess that the function of PPARs is not that well known. The modulation of PPARs probably can't be reduced to mere agonism and antagonism, which may lead to some confusion. There may be dual action subtypes like PPARG (FAAH) or PPARG (Nrf2), but PPARG is still the common denominator. PPARA and PPARB/D may also have a role, but most clues still point towards PPARG.

We propose that PPARG is a key regulator in the maintenance of peroxisomal, mitochondrial and lysosomal functions. Genetic disruption of PPARG or PPARG2 signaling in mouse prostate epithelial cells resulted in dysregulated expression patterns of peroxisomal and mitochondrial genes whose products are involved in lipid transportation and oxidation pathways. Active autophagosomes and abnormally increased numbers of lysosomes were found in PPARG- and PPARG2- deficient prostatic epithelia. In vitro these phenotypes were rescued by re-expression of PPARG1 and PPARG2 isoform in mPrE-PPARG KO cells. In vivo changes consequent to loss of PPARG were associated with hyperplasia, PIN formation and progression to malignancy, which in the case of PPARG2 suppression could be rescued using high levels of the PPARG agonist Rosiglitazone.
Alterations in lipid metabolism resulting in loss of PPARG-signaling have been suggested to predispose the prostate to premalignant or malignant changes.
Reduced PPARG function was associated with increased activation of oxidative stress, autophagic activity, and activation of pro-inflammatory signaling pathways.
This establishes conditions for subsequent malignant transformation which would be expected to occur stochastically, resulting from epithelial genomic damage potentially caused by reactive oxygen species (ROS). The results described here parallel reported changes in gene expression resulting in reduced ligands for PPARG in the human prostate and provide the first direct evidence that loss of PPARG expression or function can lead to prostatic neoplasia in vivo.
Reduced activation of PPARG due to reduced formation of endogenous ligands for PPARG most likely explains its role early in human Pca development.
Disruption of PPARG-signaling results in altered fatty acid metabolism and induction of oxidative stress and hypoxia.
Early prostate cancer has been linked to a loss of enzymes including 15-lipoxygenase-2 (15-LOX-2) which is involved in the generation of 15(S)-hydroxyeicosatetraenoic acid (15-HETE). Such a scenario justifies the consideration of PPARG agonists as chemopreventive agents to inhibit the genesis of early stage prostate cancer.

Peroxisome proliferator–activated receptor (PPAR) belongs to the steroid family receptors and is also able to bind steroid hormones. In amphibians, rodents, and humans, three forms of PPAR have been described to date: PPARA, PPARB (also known as PPARD), and PPARG. PPARs target genes that encode enzymes involved in peroxisome and mitochondria function as well as those of fatty acids, apolipoproteins, and lipoprotein lipase. Little is known about PPARs in the male reproductive system.
In rat testis, PPARs are mainly expressed in Leydig and Sertoli cells. It was shown that some PPAR chemicals alter testosterone production, and their long-term administration results in Leydig cell tumor development in rats.
It is worth noting that biosynthesis of sex steroids is multilevel, controlled process. It requires the coordinated expression of number of genes, proteins of various function [receptors, e.g., lutropin receptor (LHR), enzymes, transporters, and regulators, e.g., translocator protein (TSPO), steroidogenic acute regulatory protein (StAR)], signaling molecules (e.g., protein kinase A (PKA)], and their regulators in response to LH stimulation. Moreover, for cellular steroidogenic function, global lipid homeostasis is crucial. Perilipin (PLIN), hormone sensitive lipase (HSL), and HMG-CoA synthase (HMGCS) as well as reductase (HMGCR) are members of a cell structural and enzymatic protein machinery controlling lipid homeostasis. Activation of lipid metabolism is an early event in tumorigenesis however, the precise expression pattern of lipid balance-controlling molecules and their molecular mechanism remains poorly characterized.

Expression and activation of either PPARG 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36.
In confirmation of in vitro data, a PPARG agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARG agonization increased prostatic differentiation markers, whereas HFD downregulated PPARG-regulated genes and decreased prostate differentiation.
Epidemiological links between benign prostatic hyperplasia (BPH) and diabetes have been recognized for many years and recent studies have demonstrated that the incidence and severity of BPH are correlated with obesity, atherosclerosis, diabetes mellitus, hyperinsulinemia, hyperglycemia and hypercholesterolemia. Although diabetes mellitus has a negative correlation with the incidence of multiple cancers including prostate, diabetic patients exhibit increased mortality.
These results suggest that PPARG is a major metabolic regulator in the control of mouse and human prostate differentiation.

Upon maximal lipid storage capacity of white adipose tissue (WAT), peripheral tissues begin to store lipid in excess of their natural oxidative or storage capacity resulting in lipotoxicity, inflammation and eventually insulin resistance. Recent evidence squarely positions prostatic diseases as sequelae of systemic metabolic dysfunction, including hyperinsulinemia, hyperglycemia and hypercholesterolemia; however, the underlying etiologies of such susceptibilities remain unknown largely because of the absence of a molecular understanding of the basic metabolic machinery governing prostatic function.

In recent years, it has been shown that PPARG agonists improve different CNS dysfunctions. The antidepressant-like effects of these drugs are demonstrated for the first time by pioglitazone in a 55-year-old female who had severe unresponsive depression. NP031115, a novel thiazolidinedione, exerts antidepressant-like effect in mice, likely by inhibiting glycogen synthase kinase-3 (GSK-3) and increasing PPARG activity.
A recent study shows that polymorphism in PPARG2 is involved in depression.
Nitric oxide (NO), a signaling molecule in the nervous system, is biosynthesized endogenously from l-arginine by nitric oxide synthase (NOS). NOS family has been classified to different groups including three isoforms. Two are constitutive NOS (cNOS) and the third one is inducible NOS (iNOS). iNOS has been distinguished from cNOS being calcium insensitive. NO involved in different biological functions in CNS such as learning, memory, depression and expression of pain. It has been shown that inhibition of NOS results in antidepressant-like effect and also is involved in efficacy of various antidepressant drugs.
The role of PPARG receptors is more prominent after 2 h of PPARG agonist administration, while this effect is mediated more prominently through nitric oxide system after 4 h of pioglitazone.

In these neurons the proliferation of peroxisomes mediated by a peroxisome proliferator-activated receptor-gamma (PPARG) agonist resulted in the decrease of ROS levels. ROS are a group of highly reactive molecules, such as singlet oxygen, hydroxyl radicals, superoxide, and hydrogen peroxides. Most ROS have extremely short half-lives (nanoseconds), whereas some others, such as hydrogen peroxide, have millisecond half-lives. Due to their high reactivity, ROS can oxidize cell constituents such as lipids, proteins, and DNA, thus damaging cell structures and compromising their function. Because of these potentially noxious effects, cells maintain ROS at a tolerable level by means of antioxidants such as the redox system, superoxide dismutase, and catalase. Catalase, predominantly located in peroxisomes, catalyzes the conversion of hydrogen peroxide into water and molecular oxygen. The transcription of this enzyme is regulated by PPARG. A putative functional PPAR response element was identified at the promoter region of the rat catalase gene. Activation of PPARG by a specific agonist further enhances catalase activity and protects neurons from oxidative stress. Growing evidence indicates that endocannabinoids exhibit profound anti-inflammatory and neuroprotective properties in response to harmful insults, including oxidative stress. Some of these effects appear to be mediated by PPARG activation.
These data strongly suggest that ECs may tonically inhibit leptin-induced ROS formation, at least in vitro, and that this inhibition is under the negative control of EC degrading enzymes
It is well known that PPARG regulates a large number of enzymes, including catalase, the most important enzyme for antioxidant defense.
This observation is consistent with the hypothesis that the CB1 receptor agonist controls leptin action at least in part through PPARG activation. This nuclear receptor can directly regulate the expression of a large number of antioxidant enzymes, including catalase, which is ubiquitously expressed in the CNS and is mainly located in peroxisomes. In agreement with the report that PPARG activation by a specific agonist enhances catalase activity, thereby resulting in the protection of neurons from oxidative stress, we found here that ACEA also prevented the inhibition of catalase induced by leptin in a PPARG-mediated manner.
In agreement with the present findings in neurons, the activation of CB1 receptors was previously shown to lead to overexpression of PPARG in adipocytes. The underlying mechanism of this effect has never been investigated, but it is possible that the well known CB1-induced activation of ERKs might cause phosphorylation of C/EBPb, a transcription factor that activates PPARG, thus explaining why ACEA enhances PPARG activity also in hypothalamic neurons, which express C/EBPb.
It is possible that, like AEA (as well as other cannabinoids); it also directly activates PPARG.

PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARG agonists.
Three subtypes, designated PPARA (NR1C1), PPARD (NR1C2), and PPARG
(NR1C3) have been identified whose endogenous ligands include fatty acids and fatty acid metabolites.
PPARs form heterodimers with retinoid X receptors (RXRs) and bind to the hexanucleotidic PPAR responsive element (PPRE), thereby regulating the expression of target genes involved in lipid and carbohydrate metabolism. PPARA and PPARD agonists alone significantly reduced circulating insulin (INS) levels. The combination of the two agents not only reduced insulin but also significantly reduced triglyceride (TG) and nonesterified fatty acids (NEFAs) and elevated total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-c), and B-Hydroxybutyric acid (BHBA).
The selective PPARG agonist produced a significant reduction in circulating INS, TG, and NEFA levels. Both PPARpan agonists significantly reduced fed glucose, INS, NEFAs, and TG and increased total CHOL, HDL-c, and BHBA.
Selective activators of PPARG, such as glitazones, have been successfully used to treat T2DM for nearly a decade.
Treatment with rosiglitazone and pioglitazone induce body weight gain in mice, rats, nonhuman
primates, and humans. Weight gain is manifested as increased adiposity, total body water and plasma volume. In this report, mice treated with a potent and selective PPARG activator gained more weight than obese vehicle controls and the weight gain could be completely accounted for by increased fat mass which was equivalent to the increase in caloric intake. In addition to stimulation of
food consumption, activation of PPARG promotes triglyceride accumulation by increasing expression of genes modulating adipogenesis, lipid transport, storage, and glucose homeostasis.
In summary, PPARG agonism induces food consumption and energy storage without an effect on energy utilization resulting in net weight gain.
Activation of PPARA and PPARD receptors by PPARpan compounds may be expected to induce weight loss or provide weight maintenance while combining the beneficial insulin sensitization effects of a PPARG agonist.

Peroxisome-proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily of ligand-activated transcriptional factors, which include receptors for steroids, thyroid hormone, vitamin D, and retinoic acid. Among them, PPARG was originally characterized as a regulator of adipocyte differentiation and lipid metabolism and, more recently, of cellular turnover. Indeed, several lines of evidence indicate that PPARG profoundly affects cell cycle, differentiation and apoptosis. Thus, PPARG activation by natural or synthetic ligands such as the cyclooxygenase metabolite 15-deoxy-delta12,14 PGJ2, polyunsaturated fatty acids, different nonsteroidal anti-inflammatory drugs, and the oral antidiabetic agents thiazolidinediones favor macrophage differentiation and prevent colorectal, prostate, and breast cancer by inhibiting cell growth and accelerating apoptosis. Fibroblast, synoviocyte, macrophage, endothelial and T-cell apoptotic death in response to thiazolidinediones has also been documented.
In addition, PPARG activation downregulates the synthesis and release of immunomodulatory cytokines from various cell types.
Upregulation of PPARG expression in airway epithelium and smooth muscle of asthmatics reported in this study is reminiscent of previous observations showing an augmented PPARG immunostaining associated with the colonic epithelium in mice with an inflammatory bowel disease in rat neointima after balloon injury and in early human atheroma.
This enhanced PPARG expression may reflect an inflammatory response of different cell types and structures to natural PPARG ligands generated within the airways during the allergic reaction. Although the nature of these stimuli in the lung is unknown, it is well established that a range of naturally occurring substances, including polyunsaturated fatty acids, the 15-lipoxygenase metabolite, 15-hydroxyeicosatetranoic acid (15-HETE), or cytokines such as IL-4, are potent PPARG expression-promoting agents.
Structural abnormalities characteristic of the remodeling response in asthma involve, at least in part, a dysregulation in the proliferation and apoptosis of different cell types responsible for the maintenance of airway integrity. Of note, synthetic and naturally occurring PPARG ligands greatly ameliorate different features of tissue remodeling, including the thickening of the bowel wall in mice with inflammatory bowel diseases and arterial restenosis after endothelial injury in rats. These beneficial effects may be related to the ability of PPARG ligands to inhibit cell migration, proliferation, and proinflammatory and toxic mediator production and to promote apoptotic cell death.
Corticosteroids offer clinical improvement in airway function most likely by reducing airway inflammation, as a result of an inhibition of many transcription genes involved in the synthesis of proinflammatory lipid mediators and cytokines. Here we demonstrated that PPARG expression in the bronchial mucosa, the airway epithelium, and the smooth muscle was also downregulated in inhaled- and, to a higher extent, in oral steroid-treated asthmatics. These results indicate that the anti-inflammatory and immunomodulatory properties of these drugs may extend to the regulation of PPARG expression in target cells.
Our observations showing lower levels of PPARG in steroid-treated asthmatics are in apparent contradiction with some in vitro findings showing upregulation by dexamethasone of PPARG gene expression in human adipocytes.

In conclusion, our results identify PPARG as a new factor expressed in high levels by submucosal and structural cells during the inflammatory and remodeling response in asthma. It is difficult at this stage to anticipate a role for PPARG in human asthmatic airways. In view of the results from the literature showing the inhibitory properties of this nuclear antigen against cell differentiation, proliferation, and activation, it may be hypothesized that its upregulation in asthma would represent a self-regulatory mechanism aimed at preventing further cell activation and expansion, thus contributing to the cessation of airway inflammatory and remodeling, as proposed for other pathologic conditions. However, this classic view may be contradicted by our findings demonstrating a clear association between an augmented PPARG expression, the presence of features of airway remodeling, and the increase in bronchial obstruction. These observations, together with the efficacy of steroid therapy in downregulating PPARG expression, may lead to consider this nuclear antigen as a new mediator with proinflammatory and fibrogenic activities. This hypothesis is consistent with the expression of high levels PPARG within the atherosclerotic plaques of mice and humans and with the recent debate concerning the potential atherogenic properties of endogenously produced PPARG.

PPARs are ligand?activated receptors in the nuclear hormone receptor family. In the inflammatory response, PPARG inhibits the production of inflammatory signaling pathways and inflammatory mediators.
A previous study showed that miR?29a sufficiently suppressed the expression of CB1, which further restored PPARG signaling. The activation of PPARG, often in conjunction with the activation of CB1, could mediate the anti?inflammatory, analgesic, metabolic, neuroprotective, antitumour and cardiovascular effects of cannabinoids. However, the function and underling mechanism of CB1 in periodontal ligament stem cells (PDLSCs) in an inflammatory environment remains unclear along with its involvement in periodontal regeneration.
This study found that bacterial inflammation decreased CB1 expression in human periodontal ligament (PDL) cells. However, it has been found that CB1 seems to be upregulated during gingival wound healing in rats.
Next, we investigated the role of CB1 in PDLSCs under inflammatory conditions. The development of periodontitis is tied to the accumulation of inflammatory mediators including TNF-a and INF-g, and an increased inflammatory response develops with the destruction of periodontium tissue.
We found that the CB1 expression level in PDLSCs was decreased after stimulation with either of these inflammatory factors. A previous study found that the inflammatory factors IL?1B, IL?6 and TNF?a could enhance CB1 and CB2 expression levels in human whole blood and peripheral blood mononuclear cells (PBMCs). Upon stimulation with INF?g, no marked change was found in the expression level of CB1 in activated microglia. These findings indicate that inflammatory factors have different effects on CB1 in different cell types.
Other studies have confirmed that PPARG is a negative regulator of osteogenic differentiation. For example, a study showed that enhanced PPARG activity leads to bone loss, and reduced PPARG activity causes bone mass to increase in animal models.

We hypothesized that biosynthesis of tetrahydrobiopterin (BH4) is an important mechanism responsible for the stimulatory effects of PPARD activation on regenerative function of human EPCs. We provide compelling evidence that activation of PPARD stimulates GTPCH I expression and biosynthesis of BH4, which in turn enhances ability of EPCs to repair injured endothelium.

Cheng et al. investigated the effect of Rhodiola rosea extract on heart failure in streptozotocin-induced diabetic rats and found that both cardiac output and peroxisome proliferator-activated receptor PPARD expression level increased after treatment.
Wang et al. revealed that salidroside could promote 3 H-glucose uptake and downregulate the expression of PPARG and C/EBP-? in 3T3-L1 pre-adipocytes.
Synergistic effects of aerobic exercise and R. sacra in ameliorating skeletal and cardiac muscle damage caused by exhaustive exercise are related to the enhancement of mitochondrial quality control, partly due to the AMPK/ PPARG co-activator 1a (PGC-1a) signaling activation.
Their results showed that salidroside treatment increases the expression levels of nuclear factor (erythroidderived 2) factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and suppress NF-kB signaling, resulting in concentrationdependent decreases in reactive oxygen species (ROS) generation and increases in nitric oxide (NO) production in HUVECs exposed to AGEs.
Moreover, salidroside could alleviate high glucose induced oxidative stress and apoptosis in podocytes via the Nrf2/HO-1 signaling pathway. Additionally, as a highly inducible enzyme, HO-1 expression can be stimulated by AMPK during periods of metabolic stress.
Thus, for Rhodiola herb extract preparation, the extract solvent may determine how the extract performs, but both salidroside and other components such as phenolic compounds (tyrosol and gallic acids), flavonoid (kaempferol, proanthocyanidins, herbacetin) and polysaccharides have also been shown to protect against diabetes.
Furthermore, we found that, in HFD mice, salidroside could attenuate NAFLD via the AMPK-dependent thioredoxin-interacting protein (TXNIP)/NLRP3 pathway. Remarkably, NLRP3 infammasome is a sensor for metabolic danger and can be activated by ROS in metabolic syndrome. Once NLRP3 infammasome is activated, the active caspase-1 can process infammatory cytokine generation and exacerbate the infammatory response. We found that salidroside treatment alleviates obesity and improves the lipid proflie in serum and liver tissues as well as the ROS-triggered NLRP3 infammasome activation in the liver of HFD mice. These fndings suggested that Rhodiola and
salidroside may be suitable for the treatment of metabolic syndrome, such T2DM, atherosclerosis and NAFLD.

Taurine is abundant in the fruit of Lycium barbarum (Goji Berry).
L. barbarum extract and taurine dose-dependently enhanced the expression of PPARG mRNA and protein. In an inflammation model where ARPE-19 cells were exposed to high glucose L. barbarum extract and taurine down-regulated the mRNA of pro-inflammatory mediators encoding MMP-9, fibronectin and the protein expression of COX-2 and iNOS proteins. The predicted binding mode of taurine in the PPARG ligand binding site mimics key electrostatic interactions seen with known PPARG agonists. We conclude that PPARG activation by L. barbarum extract is associated with its taurine content and may explain at least in part its use in diabetic retinopathy progression.

The study showed anti-apoptotic activity of Lycium barbarum (Goji Berry) polysaccharides (LBP) in cultured seminiferous epithelium against hyperthermia-induced damage through the inhibition of superoxide-induced cyt c.

Tribu Saponin from Tribulus terrestris (STT) can down regulate the gene expression of ICAM-1, VCAM-1 and up regulate the gene expression of PPARA, PPARG in artery vessels of arterosclerotic rats, which may account for the anti-arteriosclerosis effects of STT.

The medicinal uses of saffron, the dried stigmas of Crocus sativus L.
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-1?, 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.
Also, some several compounds such as mineral agents, anthocyanins, glycosides, alkaloids and some flavonoids including quercetin and kaempferol not only are presents in this plant but also presents in the saffron petal. The main bioactive metabolites of the saffron spice are coming from the carotenoids.

The PPARG and -D protein levels were reduced in the SAH groups (p < 0.01). Glycyrrhizin significantly increased the expressed PPARG protein and mRNA (preconditioning) and PPARD mRNA (both treatment and preconditioning), which corresponded to the reduced IL-1? and TNF-? levels. The administration of a PPARG inhibitor, BADGE, halted the reduction of IL-1? and TNF-? in the glycyrrhizin groups. Conclusively, glycyrrhizin exerts anti-inflammatory effects on SAH-induced vasospasm and attenuates the expression of PPARs, especially PPARG, which corresponds to the severity of SAH-related inflammation. These findings also offer credit to the antivasospastic effect of glycyrrhizin and its vasculoprotective effect in animals subjected to SAH.

Quercetin and kaempferol are active components in the juice of Cape gooseberry (Physalis peruviana L.) The major phytochemical constituent’s mass spectra are kaempferol 3-O-rutinoside (1.40%), Quercetin 3,4',7-trimethyl ether (3.11%), Folic Acid (0.95%), 1,25-Dihydroxyvitamin D2 (1.27%), Lucenin-2 (1.50%), Betulin (0.62%), (5a)Pregnane-3,20-diol (0.97%). Combined treated groups marked decrease in the liver injury and collagen accumulation as compared with CCl4-treated animals.
The same mouse study found that goldenberries may increase HO-1, an antioxidant enzyme, and Nrf2, a protein that helps release defense mechanisms against tissue damage.
Besides other compounds Physalis contains rutin, myricetin, quercetin and kaempferol.

Green cardamom (Elettaria cardamomum) belongs to the ginger family, known as ‘Queen of spice’. It has anti-inflammatory and antioxidant properties. This spice is a good source of polyphenolic compounds such as quercetin, kaempferol, luteolin, pelargonidin, gallic acid, caffeic acid and limonene which have antioxidant properties. In a US patent, Pushpangadan and Prakash described a powder mixture of Piper longum fruit, Curcuma longa rhizome, Chlorophytum tuberosum and Elettaria cardamomum as an anti-diabetic herbal formulation. In an in vitro study, Ahmed et al. findings showed that by suppression of -amylase and -glucosidase activity, cardamom supplementation has anti-diabetic effects. Furthermore, some animal studies revealed that cardamom improved glycemic indices. Though, human studies that investigated the effects of cardamom are very limited. Yaghooblou et al. findings on pre-diabetic subjects showed that cardamom supplementation improved insulin sensitivity and decreased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c).
Studies have demonstrated that limonene and kaempferol which exist in cardamom can increase the activity of PPARA. Findings of a study by Muller et al.suggested that a diet rich in spice activated PPARA might contribute to blood lipid improvement.

There are a number of different long-chain fatty acids that can bind to and activate PPARD, produced in the body, or from foods. Common fatty acids from foods include polyunsaturated fats such as arachidonic acid and linoleic acid.

Results indicated that mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, and the combination of above herbs effectively reduced blood glucose, insulin, TG, and percent HbA1c in study animals (p < 0.05). We also observed that the increased expressions of liver PPARA mRNA and adipose tissue PPARG mRNA in animals fed diets supplemented with test herbs.
These results suggest that mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, and the combination of these herbs fed at the level of 0.5% of the diet significantly increase insulin sensitivity, and improve hyperglycemia possibly through regulating PPAR-mediated lipid metabolism.

Fermentation with Cordyceps militaris enhanced anti-adipogenesis efficacy of mulberry leaves.
HPLC showed that fermentation changed the contents of cordycepin, pelargonidin, chlorogenic acid, iso-quercetin and caffeic acid. Furthermore, fermented dried mulberry leaves with 50% raw silkworm pupa had a better efficacy of anti-adipogenesis than dried mulberry leaves, fermented dried mulberry leaves and fermented silkworm pupa and inhibited triglycerides accumulation and glucose consumption. Additionally, fermented dried mulberry leaves with 50% raw silkworm pupa inhibited PPARG signaling.
The 3T3-L1 cells has been widely used to research the adipogenesis when induced with insulin, dexamethasone and rosiglitazone.;year=2020;volume=13;issue=12;spage=557;epage=565;aulast=Guo
Title: Re: FAAH Inhibitors
Post by: berlin1984 on April 23, 2021, 02:55:19 PM
(Disclaimer: I have not read most of what you wrote)

How does your theory work with people that cured their POIS by improving their microbiome/gut bacteria/dysbiosis/fixing infections etc?
Title: Re: FAAH Inhibitors
Post by: Progecitor on April 25, 2021, 09:06:04 AM
There is actually a term called PPAR reprogramming which may be the singular and most important mechanism in the development of POIS.

PPARs have a role in neuroinflammation and concomitant depression!
Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies.
PPARs are a target for fatty acids (unsaturated, mono-unsaturated, and poly-unsaturated), for which they mediate binding and transport, as well as oligosaccharides, polyphenols, and numerous synthetic ligands. Furthermore, they are involved in a series of molecular processes, ranging from peroxisomal regulation and mitochondrial B-oxidation to thermogenesis and lipoprotein metabolism. PPAR distribution changes in different organs and tissues.
This antidepressant effect was also observed in clinical trials where administration of pioglitazone or rosiglitazone improved symptoms in patients with major depression. Importantly, the improvement in depression correlated with normalization of inflammatory biomarkers (e.g., IL-6) and insulin resistance, suggesting an intriguing link among PPARG-activation, depression, inflammation, and metabolism. It is remarkable that patients with high levels of neuroinflammation respond poorly to classical antidepressants, suggesting that targeting neuroinflammatory pathways may offer a therapeutic strategy to revert or alleviate mood symptoms as well. Intriguingly, dietary interventions have been tested in several neuropsychiatric disorders, such as multiple sclerosis (MS), anxiety, and depression. As molecular targets for various natural ligands found in a number of aliments, PPARs may shed light into the molecular mechanisms underlying the success of dietary treatments in nutritional psychiatry.
The nuclear receptors PPARA and G are gaining consistent interest as new promising targets for treating behavioral dysfunction. This is further substantiated by the recent discovery that stimulation of PPARA can enhance neurosteroid biosynthesis, which is implicated in the etiopathology of mood disorders and their treatment.
Both genetic or pharmacological inhibition of PPARA blocks the anti-depressive effects of fluoxetine, thereby suggesting its involvement in the molecular mechanisms of antidepressant drug action.
The main PPARA endogenous agonist, N-palmitoylethanolamine (PEA) is an anti-inflammatory, analgesic, and anti-allergic compound clinically tested for its neuroprotective effects in multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). PEA can be produced endogenously or acquired through plant-based food sources and it is endogenously metabolized by the fatty acid amide hydrolase (FAAH), which is an enzyme involved in the metabolism of endocannabinoids, including anandamide (AEA). As an endogenous ligand, PEA activates the G-protein coupled receptor, GPR55, while showing low affinity for the cannabinoid receptor type-1 (CB1) and type2 (CB2). However, its therapeutic behavioral effects appear to be mediated via PPARA binding and activation. PEA administration in socially isolated mice, a model of protracted stress-induced PTSD, normalized reduced brain levels of allopregnanolone, a GABAergic neurosteroid, which is found decreased in patients with depression and PTSD. In the socially isolated mouse, PEA improved contextual fear responses and facilitated contextual fear extinction and fear extinction retention, as well as ameliorated depressive-like and anxiety-like behavior by increasing corticolimbic levels of allopregnanolone. Consistently, in a cohort of Ugandan war survivors affected by PTSD, the hair levels of PEA, oleoylethanolamide (OEA), and stearoylethanolamide (SEA) were found to be decreased when compared with levels of war survivors without current or lifetime PTSD, thus suggesting a decreased PPARA signal pathway in PTSD. While it is important that these findings will be confirmed also in blood and post-mortem brain of PTSD patients, this observation provides support to the involvement of the PPAR-allopregnanolone axis dysfunction in PTSD. Together with the findings that allopregnanolone has been found decreased in cerebrospinal fluid (CSF) and plasma of both male and female PTSD and MDD patients, these clinical data provide a translational example with PTSD animal models.

In peripheral blood mononuclear cells (PBMC) extracted from chronic schizophrenic patients, a decreased expression and activity of PPARG correlated with lower plasma levels of its endogenous ligand, 15d-prostaglandin J2, which overall indicates a state of increased inflammation. Another study in patients affected by schizophrenia investigated the expression of inflammatory and metabolic genes. Expression of PPARG was increased while PPARA was decreased, suggesting a metabolic-inflammatory imbalance in schizophrenia. Pioglitazone provided benefits in reversing this metabolic condition.
Autism spectrum disorder (ASD) is also characterized by neuroinflammation, oxidative stress and depletion of glutathione in the brain. In clinical studies, pioglitazone was tested in a 16-week prospective cohort of 25 autistic children, showing good tolerability and leading to a statistically significant improvement in repetitive behaviors, social withdrawal, and externalizing behaviors.
A natural ligand of PPARG is resveratrol, which is also able to prevent social behavioral impairments in a rodent ASD model.
Consistent with a PPARA activation, neurobehavioral and biochemical benefits in an ASD animal model were observed following administration with fenofibrate that resulted in reduced oxidative stress and inflammation in several brain regions. PEA reverted the altered phenotype and improved ASD-like behavior through a PPARA activation. This effect was accompanied by decreased levels of inflammatory cytokines in serum, hippocampus, and colon. PEA administration restored the hippocampal BDNF signaling pathway in BTBR mice and improved mitochondrial dysfunction, which has been observed in ASD.
A PPARA-allopregnanolone (i.e., endocannabinoid-like/neurosteroids) cross-talk may have an impact for establishing relevant novel targets for the treatment of PTSD and major depression. Intriguingly, these newly observed link between the endocannabinoid-like system and biosynthesis of neurosteroids may additionally provide bio-signatures for the diagnosis and treatment of psychiatric disorders, which still rely on subjective measures based on the DSM-5 criteria. Furthermore, PPARG agonists, including pioglitazone, have shown promising antidepressant effects in several clinical trials. It is also remarkable that non-steroidal anti-inflammatory drugs, including ibuprofen and aspirin, whose mechanism of action includes a PPARG activation, have consistently shown potent antidepressant effects.
Wnt/beta-catenin is downregulated when PPARG is upregulated in AD. Imbalance in the Wnt/beta-catenin/PPARG regulation plays a role in physiopathology of neurological disorders owing to its involvement in oxidative stress and cell death through regulation of metabolic enzymes. Administration of pioglitazone in a genetically modified AD mouse model showed reductions in both soluble and insoluble amyloid B, while improving memory, learning deficits, and preventing neurodegeneration. However, in clinical studies, pioglitazone showed no significant effects on cognitive outcomes. indicating a role, not only for PPARG, but also for PPAR-B/D in the pathology of AD. On the other hand, activation of PPARA by PEA has proven efficacy in inhibiting amylogenesis, neuroinflammation, neurodegeneration and Tau hyperphosphorylation. The AB-induced tau protein hyperphosphorylation is also reduced by cannabidiol (CBD) administration, through the PPARG and Wtn/B-catenin stimulation, which underscores a role for this phytocannabinoid in reducing neuroinflammation and oxidative stress.
This finding suggests that resveratrol and other compounds, which act on PPARG and PGC-1a might be beneficial as therapeutic agents in PD pathophysiology and possibly in other neurological disorders.
PPARA also plays a role in the duration and occurrence of seizures (measured by a spike-wave discharges on EEG recordings) in WAG/Rij rats, one of the most used models of human absence epilepsy, where PEA attenuates seizures by binding PPARA and indirectly by activating the CB1 receptor.

Check out Figure 1!

PPARs have a considerable role in withdrawal!
Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPARA and PPARG isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding.
Substance use disorders (SUDs) continue to represent a significant global public health burden.
For example, while the focus of early addictions research was the acute, positively reinforcing properties of drugs of abuse, it is now recognized that negatively reinforcing states involving anhedonia, dysphoria, and anxiety become more important in maintaining drug-taking over time. As a result, motivation to use the drug shifts from seeking pleasure to avoiding negative affect.
Agonist substitution therapies have been successful in mitigating this negative reinforcement in some SUDs, e.g., methadone or buprenorphine for managing withdrawal and craving associated with opioid use disorder and nicotine replacement therapy (NRT) for managing nicotine withdrawal. Other medications, such as naltrexone or acamprosate for alcohol use disorder and varenicline or bupropion for nicotine dependence, have demonstrated some efficacy in reducing positive and/or negative reinforcing aspects of drug use.
While PPARs were initially identified as lipid sensors, burgeoning evidence has demonstrated a role of these nuclear receptors in a wide range of physiological functions, including central nervous system (CNS) functions such as memory consolidation and modulation of pain perception.
PPAR agonists have been recently considered for their potential to treat neuropsychiatric disorders, largely due to their ability to target levels of neuroinflammation thought to be involved in the pathophysiology of these illnesses. In particular, mounting evidence of an important relationship between neuroimmune function and addiction-related processes has generated interest in investigating the role of PPARs in drug-related behaviors.
Converging lines of evidence have also suggested a more direct role of PPARs in addiction-relevant neurocircuitry. Initial evidence came from studies demonstrating that selective inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for degradation of the endogenous cannabinoid anandamide and the endogenous PPAR ligands oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), could suppress nicotine-induced activation of dopamine neurons in rats. Importantly, this effect was mimicked by OEA and PEA, but not anandamide, suggesting the effect was due to PPAR activation specifically. Exogenous PPAR agonists have also been demonstrated to attenuate nicotine-induced and heroin-induced excitation of dopamine neurons in the ventral tegmental area (VTA) and elevations of dopamine in the nucleus accumbens (NAc) shell in rats. Further confirmatory evidence comes from rodent studies demonstrating that PPAR isoforms are indeed localized in addiction-relevant brain regions such as the VTA, an important part of the mesocorticolimbic dopaminergic system that plays a central role in drug-related reward, and that PPARG colocalizes with tyrosine-hydroxylase-positive cells in the VTA, suggesting direct expression in dopaminergic neurons.
A significant body of evidence has consistently demonstrated that PPARA agonists can attenuate voluntary consumption and operant self-administration of ethanol in rodents. Using the two-bottle choice paradigm, studies have found a decrease in voluntary consumption of ethanol following administration of the clinically useful drugs gemfibrozil and fenofibrate, the endogenous agonist OEA, the experimental agonist WY14643, and the dual PPAR-A/G agonist tesaglitazar.
Conflicting evidence exists regarding how PPARA agonists influence withdrawal from ethanol. Bilbao et al. (2016) found that i.p. injection of 5 mg/kg of the endogenous PPARA agonist OEA significantly reduced total ethanol withdrawal scores in male rats, and furthermore decreased each of the individual withdrawal signs evaluated (vocalizations, head tremor and rigidity, tail tremor, and body tremor). Blednov et al. (2016) found that oral administration of 150 mg/kg fenofibrate or 1.5 mg/kg of the dual PPAR-A/G agonist tesaglitazar actually increased withdrawal severity (handling-induced convulsions score) in male (but not female) mice. The results of these two studies are difficult to compare given the different choices of PPARA agonist, dose, and route of administration, withdrawal signs evaluated, and animal models, but do suggest some role of PPARA in modulating ethanol withdrawal.
Two studies have suggested a role of PPARA agonists in reducing nicotine withdrawal signs. Jackson et al. (2017) assessed the impact of PPARA agonists on symptoms of precipitated nicotine withdrawal. They observed that WY14643 attenuated anxiety-like behaviors, hyperalgesia, and somatic withdrawal signs, while fenofibrate attenuated only somatic withdrawal signs.
Finally, two studies have provided evidence that PPARA agonists can block reinstatement of nicotine-responding following a period of extinction. The reduction in withdrawal symptoms and the attenuation of both drug- and cue-induced reinstatement suggest that PPARA agonists may be useful in preventing relapse in nicotine-dependent smokers.
Similar to the evidence for PPARA agonists, the results of several studies support a role of PPARG agonists in attenuating voluntary consumption and operant self-administration of ethanol.
Two studies have suggested that PPARG agonists can attenuate behavioral sensitization to stimulant drugs.

However, when pioglitazone was co-administered with naltrexone, there was an attenuation of cue-induced reinstatement. These results suggest that PPARG agonists may be useful in preventing alcohol relapse, possibly to a greater extent when administered concurrently with naltrexone, a non-selective opioid receptor antagonist that is already approved by the United States Food and Drug Administration (FDA) to treat alcohol use disorder.
The majority of the preclinical behavioral evidence suggesting a role of PPAR agonists in addiction-like behaviors has focused on ethanol. Currently, the literature strongly supports a role of PPARA agonists (gemfibrozil, fenofibrate, OEA, and WY14643), and PPARG agonists (rosiglitazone and pioglitazone) or a dual PPAR-A/G agonist (tesaglitazar) to a lesser extent, in attenuating the voluntary consumption and reinforcing properties of ethanol in rodents. Limited evidence suggests that the PPARA agonist fenofibrate may additionally reduce the rewarding properties of ethanol, as assessed in the CPP paradigm. While agonists at both PPARA (OEA and fenofibrate) and PPARG (pioglitazone) seem to have some role in modulating ethanol withdrawal signs, the nature of this role is unclear. However, the evidence does suggest that PPAR agonists may be useful in reducing the likelihood of alcohol relapse after a period of abstinence. PPARA agonists (OEA and WY14643) were shown to attenuate cue-induced reinstatement of ethanol-seeking, while a PPARG agonist (pioglitazone) was shown to attenuate stress-induced reinstatement (and possibly also cue-induced reinstatement when co-administered with naltrexone).
Robust evidence from a limited number of studies strongly supports a role of PPARA (and possibly PPARG) agonists in modulating nicotine-related behaviors in both rodents and non-human primates. The PPARA agonists methyl-OEA, WY14643, and clofibrate were found to reduce the reinforcing properties of nicotine. In addition, WY14643, fenofibrate, and OlGly were found to reduce the rewarding effects of nicotine in the CPP paradigm. WY14643 was shown to decrease behavioral and somatic signs of nicotine withdrawal, while both WY14643 and clofibrate reduced drug- and cue-induced reinstatement of nicotine-seeking. Finally, the PPARG agonist pioglitazone reduced somatic and anxiety-like signs of nicotine withdrawal.
Preliminary evidence suggests that PPARG agonists may have a role in modulating opioid-related behaviors. Studies found that pioglitazone was able to reduce the reinforcing effects of heroin in an operant self-administration paradigm, decrease both drug- and stress-induced reinstatement of heroin-seeking, and reduce the development and expression of morphine tolerance and withdrawal.
Finally, there seems to be a role of PPAR agonists in psychostimulant-related behaviors, yet the evidence is mixed. The PPARG agonists ciglitazone and pioglitazone attenuated behavioral sensitization to methamphetamine, while pioglitazone attenuated behavioral sensitization to cocaine.
Additionally, the endogenous PPARA agonist OEA attenuated behavioral sensitization to cocaine and cocaine CPP, but through a PPARA-independent mechanism. However, it is important to note that studies of nicotine-related outcomes found no effect of PPARA agonists on operant self-administration of cocaine or cocaine CPP.
As discussed previously, pioglitazone was more effective in reducing reinstatement to ethanol-seeking when it was co-administered with naltrexone, an opioid receptor antagonist, suggesting some degree of synergy between PPAR activation and opioid receptor inhibition. Similarly, it has been proposed that simultaneous inhibition of FAAH and activation of PPARs may have an additive or even synergistic effect in treating cancers, and this approach may similarly hold promise in the context of addiction pharmacotherapy.

Antibiotics and changes in microbiome also modulate PPARG!
Using fecal transplant procedures we reveal that, in response to high?fat diet, the gut microbiota drives PPARG?mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARG?driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.
Notably, high?fat feeding was shown to amplify the expression of PPARG and its target genes by inducing de novo cyclic recruitment of PPARG to chromatin. Our results show that gut microbial remodeling under high?fat feeding induces rhythmic activation of PPARG that in turn leads to transcriptional reprogramming in the liver.
Circadian activation of PPARG and SREBP1 expression coordinately contributes to the regulation of hepatic lipid metabolism in HF?R mice and previous evidence demonstrates that metabolites produced by gut microbes regulate host liver lipogenesis. Indeed, we observed an increase in the levels of hepatic long?chain fatty acids that are involved in both signaling pathways and in lipid accumulation in the liver. Furthermore, short?chain fatty acids (SCFA) produced by bacterial fermentation are modulators of PPARG, and PPARG signaling might be altered by different SCFA profiles depending on dietary changes.

Environmental pollutants modulate PPARG!
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that are widely involved in various physiological functions. They are widely expressed through the reproductive system. Their roles in the metabolism and function of sex steroids and thus the etiology of reproductive disorders receive great concern. Various kinds of exogenous chemicals, especially environmental pollutants, exert their adverse impact on the reproductive system through disturbing the PPAR signaling pathway. Chemicals could bind to PPARs and modulate the transcription of downstream genes containing PPRE (peroxisome proliferator response element). This will lead to altered expression of genes related to metabolism of sex steroids and thus the abnormal physiological function of sex steroids.
PPARs are detectable in various compartments of the reproductive system, including hypothalamus, pituitary, testis, ovary, uterus, and adrenal and mammary gland.
PPARs are widely involved in reproductive function, such as ovarian function, gestation, and communication between mother and fetus. Sex steroids, also named as gonadal steroids, are defined as steroid hormones that interact with receptors of androgen, estrogen, and progesterone in vertebrates. Sex steroids are produced by gonads (ovaries or testes) and adrenal glands. Further conversion could occur in other tissues such as livers and fats. PPARs are critical for the metabolism and physiological function of sex hormones.
Pollutants could bind to PPARs and then modulate the PPAR signaling pathways involved in the reproductive function.
Hydrophobic interactions are the primary driving force for the binding between pollutants and PPARs. Most of the amino acid residues are hydrophobic around the binding pocket which located inside the protein structure of PPARs. The sequences of amino acids which form the pocket are conserved across species. Results from reporter cell lines also show that environmental ligands (BPA derivatives, phthalates, and PFAAs) share similar affinity for PPARG of zebrafish and human.
Exogenous testosterone significantly inhibited the expression of PPARG in primary hepatocytes isolated from brown trout. 17B-Estradiol could regulate the expression of PPARG in human peripheral blood eosinophils. Additionally, precursors of sex steroids also interact with PPARs. For example, dehydroepiandrosterone (DHEA) induced elevated expression of both PPARA and PPARB/D in the muscle of mice. Conversely, PPARs have an important impact on sex steroids.
Peroxisome proliferators (PPs) are a group of chemicals which function through PPARs. PPs could impair the function of endocrine tissues by regulating the expression of phase I and phase II steroid metabolism enzymes, including P450 enzymes and 17B-hydroxysteroid dehydrogenase IV. Apart from their impact on metabolism, PPs could also disturb the physiological function of sex steroids. They have been reported to mimic or interfere with the action of sex steroids and then induce reproductive disorders. In addition, receptors of sex steroids were also reported to interplay with PPARs. For example, estrogen receptor alpha (ERa) binds to the PPRE sequence of PPARG and represses its transactivation in MCF-7 cells. Bidirectional interplay occurs between PPARG and ER.
Sources of PPs contain endogenous and exogenous chemicals. Endogenous essential fatty acids (FAs) and their derivative eicosanoids are able to activate the PPAR signaling pathway. 17B-Estradiol could suppress the expression of PPARA regulating genes. In addition to these endogenous chemicals, chemicals from environmental media, drugs, and other external sources are also reported to disturb the PPAR signaling pathway and then affect metabolism and function of sex steroids.
PPARs have been regarded as a bridge to link the environmental chemicals and their health impact.

Some environmental pollutants that modulate PPAR activity are phthalates, perfluoroalkyl acids (PFAAs), bisphenol A (BPA), dioxin, some pesticides etc.
In addition to individual pollutants, chemical mixtures also display reproductive toxicity through PPARs. Direct activation of AHR and transactivation of PPARs are indispensable parts in this molecular response pathway.
PPARs, especially the subtype of A and G, have important roles in mediating the toxicological outcomes caused by environmental ligands. Various kinds of environmental pollutants show impacts on the metabolism and function of sex steroids through disturbing the PPARs signaling pathways.

Arg1 induction was accompanied by enhanced expression of the nuclear receptor peroxisome proliferator?activated receptor gamma (PPARG), and by enhanced IL?10 release, known markers of pro?regenerative microglia.
The transcription factor STAT 6 accumulates in response to IL?4 and, along with its downstream effector PPARG, has a central role in the regulation of transcription of anti?inflammatory and pro?resolving genes. Additionally, IL?4 induces expression of CD36, a receptor of lipoproteins, whose uptake and metabolism may support fatty?acid oxidation, contributing to metabolic microglia reprogramming.
IL?10 drives microglia toward an alternative activated phenotype, which mainly participates in phagocytosis and removal of tissue debris.
As mentioned above, PPARs-G are nuclear receptors highly expressed in microglia, that play important roles in both the immune response and cell metabolism.
Consolidated evidence indicates that PPARG activation by both natural and synthetic agonists, including the small molecule SNU?BP, inhibits expression of surface antigen and synthesis of inflammatory mediators, while increases the expression of the anti?inflammatory genes Arg?1 and IL?4 and promotes microglial phagocytic ability.
PPARs-G have been implicated in the phenotypic switch induced in microglia by some neuroprotective natural compounds, such as malibatol A, a resveratrol agonist and galangin, a molecule abundant in honey and medicinal herbs (such as galangal!).
PPARG?dependent microglia reprogramming toward beneficial function accounts for better outcome in several preclinical models of brain pathologies. The treatment of AD mice with the PPARG agonist pioglitazone, a drug used to treat type 2 diabetes, results in enhanced capability of microglia to phagocyte AB and cognitive improvement. Moreover, pioglitazone ameliorates the disease course in both the experimental autoimmune encephalomyelitis (EAE) model of MS and in mice subjected to chronic mild stress.
PPARs-G regulate inflammatory pathway in microglia by several mechanisms. They block p?38MAPK inflammatory pathways, resulting in decreased microglia reaction and reduce the activation of the classical pro?inflammatory transcription factors STAT?1 and NF?kB, which are known to mediate both LPS and IFNg inflammatory signaling in microglia. However, the pivotal role of PPARs?G in regulating the activation state of microglia may be due to metabolic reprogramming, as recently highlighted in macrophages, where PPARG has been implicated in mTOR?dependent fatty acid uptake and lipid metabolic reprogramming, downstream activation of semaphorin 6D (Sema6D), a key regulator of alternative macrophage polarization. Indeed, through interaction with downstream transcription factors and coactivators, PPARs?G regulate the expression of genes involved in glucose metabolism in mitochondria and fatty acid oxidation. Specifically, when activated by the full agonist pioglitazone, PPARs-G increase mitochondrial biogenesis, mitochondrial DNA content and oxygen consumption through interaction with the PPARG coactivator 1?alpha (PGC1a), the nuclear factor erythroid 2–related factor 1–2 (Nrf1–2), and mitochondrial transcription factors (mtTF)A, regulating antioxidant gene expression. In addition, PPARG activation increases mithocondrial fission, which mediates removal of damaged mitochondria and plays an important role in the assembly of mitochondrial electron transport chain.
Independent of the inflammatory challenge applied (e.g., hypoxia, interferon?g, amyloid?B), cultured microglia consistently show decreased production of pro?inflammatory factors, decreased COX2 and iNOS activity while exibit typical features of anti?inflammatory microglia, like CD206 surface expression and autophagy when treated with n?3 PUFAs.
Inhibition of p38MAPK inflammatory pathway and PPARG activation are also in part responsible of protective effects of PUFAs and their products. Given the connection of NF?kB and PPARG to the bioenergetics state of microglia, also dietary lipids may likely shape microglia phenotype acting on cell metabolism. In support to this hypothesis, fasting and ketogenic diet, that lead to a sustained reduction in blood glucose levels and to an increase in circulating ketones, have been reported to have anti?inflammatory actions and suppress activation of microglia by regulating their metabolic features. These effects have been shown to rely on the activation of the metabolite receptor GPR109A by B?hydroxybutyrate, that attenuates NF?kB signaling and pro?inflammatory cytokine production.
Other groups of bioactive compounds, normally present in foods, especially in the Mediterranean diet, such as phenolic compounds, phytosterols and carotenoids (e.g., lycopene, fucoxanthin, and lutein) exhibit anti?inflammatory properties on microglia, but the mechanisms underlined their effects still remain to be defined.
(Micro RNA) MiR?223 deficiency leads to compromised pro?regenerative differentiation in response to IL?4. Importantly miR?223 has been shown to be required for PPARG function, linking the acquisition of pro?regenerative traits to mitochondrial glucose metabolism and fatty acid beta oxidation.
miR?181a targets the inflammatory genes IL?1?, TNF and the transcriptional factor C/EBPa but also suppresses Kruppel?like factor 6 (KLF6), a PPARG inhibitor, thus likely favoring PPARG?dependent energy metabolism in mitochondria and fatty acid peroxidation in microglia. This has been proven in lymphocytes where miR?181a enhances the expression of genes involved in beta oxidation while suppresses isocitrate dehydrogenase 1 (IDH1), a cytoplasmic enzyme involved in production of NADPH, the cofactor for NO and superoxide generation.
Previous findings from our group and others have shown that through their secretome mesenchymal stem cells (MSCs) re?direct microglia from detrimental toward pro?regenerative functions.
MSCs, indirectly co?cultured with microglia in vitro, directly counteract the pro?inflammatory response of cells activated with inflammatory cytokines and induce persistent pro?regenerative traits.
Pluchino and colleagues clearly showed that NPCs counteract the metabolic changes of pro?inflammatory cells and reprogram them toward an oxidative phosphorylation anti?inflammatory phenotype. Indeed NPCs restore basal oxygen consumption rate and extracellular acidification rate in pro?inflammatory macrophages. Furthermore, by performing an untargeted mass spectrometry analysis of the extracellular and intracellular metabolite content of macrophages, they identified the metabolite succinate as the main target of the pro?regenerative NPC action. Intracellular succinate is known to act as a key pro?inflammatory signal in phagocytes, by enhancing IL?1B generation and favouring mitochondrial production of ROS over ATP synthesis. Extracellular succinate also exhibits pro?inflammatory activity though interaction with its specific receptor SUCNR1 and it is emerging as a biomarker of metabolic distress and inflammatory activity.
PPARG activation is an alternative way to push oxidative metabolism in microglia, as already mentioned. PPARs?G can be activated with thiazolidinediones (e.g., pioglitazone or rosiglitazone) a class of antidiabetic drugs proven to be effective in reducing the extent of neuroinflammation in different models of brain diseases and to attenuate neurodegeneration in patients with mild?to?moderate dementia.
Starting from Resveratrol, the first SIRT1 activator described, other SIRT activators have been developed and some of them are currently in clinical trials for the treatment of age?related neuroinflammation.

Also check out the figures!

L-theanine inhibited the absorption of glutamine and large neutral amino acids (AAs, leucine, and tryptophan) into organs.
It is reported that the fatty acid accumulation in mice was suppressed by the administration of green tea powder and theanine was responsible for this suppressive effect. Although serum glucose in rats was not changed, the insulin was reduced by oral theanine. These literatures indicate that metabolism of lipid and insulin is regulated by L-theanine. Therefore, we predicted that L-theanine may target transcription factors (PER1, HNF, and PPARG) and further inhibit the expression of glucose transporters mRNA.

Title: Re: FAAH Inhibitors
Post by: Progecitor on April 29, 2021, 08:23:51 AM
(Disclaimer: I have not read most of what you wrote)

How does your theory work with people that cured their POIS by improving their microbiome/gut bacteria/dysbiosis/fixing infections etc?

I am sorry for not replying earlier, but I needed some break.
Regarding your question I was actually getting to that point, but I had to lay out some background information first. From the previous post it is fairly reasonable to assume that a change in microbiome can lead to sustained PPARG reprogramming. This might have happened in the case of the POISer who eradicated most of his microbiome and reestablished it with a different set. This may be similar to fecal transplantation. Actually there is no guarantee that this could work, as I also took Ciprofloxacin with a probiotic for 10 days and it hadn't resolved my POIS issue. I also had controversial experiences with probiotics. Some probiotics containing Lactobacillus actually increased the burning pain and that is why I suspected the involvement of lactic acid. Other probiotics caused severe flatulence which I considered a bad reaction at the time, although I am not so sure anymore. I haven't documented their effects at the time, but I will retest them based on the new findings.

(I read about these supposedly cured cases of POIS on the forum a few weeks ago, but I couldn't find the link right now. I also don't know how credible they were.)

The other POISer who got cured through abstinence may have undergone a similar PPAR reprogramming as PPARs also play a role in withdrawal which definitely seems to be linked to our case. However there is still no guarantee that POIS can be resolved in every case, especially if there is an underlying genetic issue.
I am at least quite certain that regular ejaculation won't lead to POIS cessation, although some degree of tolerance may develop due to it. The longest period I abstained from sexual activity was more than half a year, but that also didn't change POIS.
Maybe some prolonged change could be achievable by abstaining and still taking the best working medication. Even if this is feasible there is still the issue of enhancing foods which doesn't make this easy and a result could be ill-hoped.

Other POISers managed to resolve their case by curing a localized inflammation. This also seems to be in line with the role of PPARs in inflammation. However identifying the exact site of such an inflammation is rather problematic with current diagnostic methods.

Of course these are only possibilities and the role of PPARs is not even proven yet. I am going to continue to trial as many supplements as possible so that some further conclusions may be drawn.

However if the role of PPARs is proven some other novel treatment possibilities arise actually.
It may be possible that a stem cell treatment could also ablate the inflammation, however I think we are decades if not centuries from such a treatment.

Some experiences I had in the meanwhile:
The combination of lungwort tea and saffron is quite extraordinary. Unfortunately even this can't completely overcome POIS, but this is the best thing I have found so far. It reduces all aspects of POIS considerably. It is definitely a profound painkiller. It feels like most of my pain receptors are blocked. I can only imagine that a very high anandamide level desensitizes TRPV1 receptors. I can hardly feel the thighs and my dick feels like a limp mass. Well it probably shouldn't be used if someone actually wants to do sex, but it is a superb after-event treatment nonetheless. If any POISer doesn't have any positive reaction to this I can't imagine their case has anything to do with the endocannabinoid system or with FAAH inhibitors at least.

I bought a supplement containing Echinacea and beta glucan [Echinacea purpurea 450 mg per pill and oat (Avena sativa) extract 50 mg per pill].
I took one pill in the morning and also took some separate Echinacea drops. Then I took two pills an hour before watching porn. Interestingly porn couldn't arouse me which is rare and I had to use physical stimulation to get an erection, although I am not sure if it was due to the supplements. POIS still occurred at O, but this managed to reduce POIS symptoms noticeable. I also took one pill before going to bed. Its effectiveness is somewhat below that of Berberine, but it certainly works.
I also tried the Echinacea drops [Echinacea angustifolia and Echinacea pallida alcoholic tincture 1g containing 0.33 g Echinacea] separately on an acute day without O. I took 20-30 drops with several hours of difference 4 times a day. It definitely reduced the burning pain if nothing else, although it takes about 6 hours to have this effect. I still had bloodshot eyes however and I can only hope it wasn't due to Echinacea itself.

Niacinamide (Vitamin B3) [500 mg per pill]: It certainly has a positive effect. Although I didn't test this against an O, taking one pill certainly reduced the burning pain by next day. It didn't have any particular side effects, aside from the mild hot flash that appeared in about 40 minutes. I would put its efficacy around that of ibuprofen. Next time I will take two pills and check it against an O.

I tried Rhodiola rosea on its own without an O. I took two capsules in the afternoon then one before going to bed. However I couldn't judge if it had any particular positive or negative effect. I will need to test it further.

I took a soy lecithin supplement a few years ago, but I can't remember if it did anything profound. As lecithin is a good source of PEA (Palmitoylethanolamide) I think I should try it again and see if it works better in a combination.
PEA is a naturally occurring lipid discovered more than 50 years ago, when it was first isolated from soy lecithin, egg yolk, and peanut meal. It is a long-chain N-acylethanolamine (NAE) and analog of the endocannabinoid anandamide (AEA) that is present in animals and plants.

Actually I tested a lot of other things in the meanwhile, but the effects are not always evident especially if they are adverse or mixed.
Melatonin and bitter melon looks to be promising, but I still need to test them a bit more to say anything definite.

I also have to wonder why so many anti-cancer drugs work in my case. If nothing else this may further reinforce the role of PPARs as new research (see a previous post) highly indicate their involvement in cancer development and treatment.

Another interesting experience I had was on a chronic POIS day when in the morning I drank saffron tea and also took a berberine and MACA capsule. I was feeling rather well even in the afternoon. Then I decided to watch porn and masturbate, but I didn't take anything beforehand. It was like more than half an hour when I went to the bathroom for some water. I checked in the mirror and had completely clear (white) eyes. I went back and not another 10 minutes later (without O) suddenly there is a stinging pain in the eyes. I went to check in the mirror and I had full blown bloodshot eyes. So even if I use a well working treatment there seems to be an extent to their effect. So to put it in a different way POIS is much like the surging waves of the ocean while the treatment acts much like a dam. The problem is that the waves are incessantly eroding the dam and a fragile dam simply can't withstand the onslaught of the tsunami that comes at the moment of O. To prolong the drowning the ocean doesn't become still after the tsunami, but actually gets stormy and turbulent for a week and even the best dams I quickly put in its place are rapidly pulverized.
Title: Re: FAAH Inhibitors
Post by: berlin1984 on April 30, 2021, 02:07:39 PM
The combination of lungwort tea and saffron is quite extraordinary. Unfortunately even this can't completely overcome POIS, but this is the best thing I have found so far. It reduces all aspects of POIS considerably. It is definitely a profound painkiller. It feels like most of my pain receptors are blocked. I can only imagine that a very high anandamide level desensitizes TRPV1 receptors. I can hardly feel the thighs and my dick feels like a limp mass. Well it probably shouldn't be used if someone actually wants to do sex, but it is a superb after-event treatment nonetheless. If any POISer doesn't have any positive reaction to this I can't imagine their case has anything to do with the endocannabinoid system or with FAAH inhibitors at least.

Random googlings because somewhere in forum it was mentioned that acetylcholinesterase inhibiton (and choline supplementation?) helps, someone with more science knowledge please confirm if relevant:

Pulmonariae officinalis (Lungwort) (Apparantely there are multiple lungworts, so NOT Lobaria pulmonaria)
The P. officinalis extracts showed slightly lower acetylcholinesterase inhibitory effects – 87.7%, tyrosinase inhibitory effects – 73.69%,

Saffron extract showed moderate AChE inhibitory activity (up to 30%),

I wonder about the chest pain you describe. I never have chest pain. Maybe the tea fixed something there for you if it claims it's for chest infections. Also claims it's for urinary tract infections

When reading Amazon reviews for teas with Lungwort, they say it really helped their breathing.
And in the forum here we sometimes discuss about breathing techniques or autonomic nervous system... hmmm very interesting.
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 02, 2021, 05:35:17 AM
Hello Progecitor, did you see that I sent you a personal message?

I am sorry for the late response, but I haven't had much spare time. Nevertheless I put the reply here so that others may also find some benefit.
Prospero was kind enough to bring to my attention that the PPAR-allopregnanolone axis could have a connection to Gilbert's syndrome.
"In Gilbert's your hormones are not knocked down, you have problems with glucuronidation, which breaks down 3adiol. So your 3adiol is not broken down, which inhibits 5a-reductase and causes low allopregnanolone, which leads with time to GabaA downregulation and AMPA receptor upregulation. Your high glutamate leads to activation of microglia. These problems with liver also stop methylation, which will be worsened because you are homozygous for COMT, and then you have bad conversion from noradrenaline into adrenaline. And obviously problems with histamine, serotonin, etc."

I checked into it a bit, but the involvement of GABA seems controversial so far. You could be right, but I don't have any hormonal measurements and I haven't tried many GABAergic compounds either. I plan to have some hormonal tests done later this year and maybe some genetic tests next year, but the pandemic and my earnings don't make this easy. I highlighted some definitions as I am also just learning about these things and it makes this a bit easier to understand.
What I found so far:
3a-diol is a positive allosteric modulator of the GABA(A) receptor which means that it changes the receptor's response to stimulus. Positive modulators increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both.[/i]

I checked the list on wiki and the comments I can make:
GABA(A) agonists: GABA, taurine, beta-alanine, allopregnanolone
GABA: I plan to buy to buy a supplement, but it hasn't been a priority so far.
Beta-alanine didn't do anything to POIS or my depression although I took it for two months last summer. Taurine increases the burning pain I feel which is a major indicator of my POIS. It can also cause a heartburn. However I haven't noticed any effect on depression or I was just not aware enough.
GABA(A) positive modulators: benzodiazepines, apigenin, niacinamide, 3a-diol, allopregnanolone
I took clonazepam (benzodiazepine) for years and it surely made me even more depressed and forgetful, however I don't think it really affected the other aspects of POIS or I just can't remember.
Apigenin and niacinamide are actually beneficial for my POIS.
Antagonists: I couldn't find any that is readily available to check.
Negative modulators: DHEA, amentoflavone, ciprofloxacin
DHEA,: I haven't tried it yet but I want to in the future.
St. John's Wort (SJW) contains amentoflavone. I tried SJW twice, but I also took other POIS modulators at the time so I can't conclude anything yet.
Ciprofoxacin: I took some a few years ago, but I don't think it did anything to depression or I just don't remember.

I actually bought an Apigenin product that also contains taurine. I only took it once, but I don't think it did much. This should theoretically up-regulate GABA(A) quite well. I am going to test it a bit more of course, but others could do as well.

Lemon balm (Melissa officinalis) is a GABA transaminase inhibitor. Inhibition of GABA transaminase enzymes reduces the degradation of GABA, leading to increased neuronal GABA concentrations.

It is true that both apigenin and lemon balm help me, but they are also involved in FAAH inhibition.

The most potent and selective inhibitors of 5a-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea. Riboflavin was also identified as a 5a-reductase inhibitor.[/b]
It is a fairly reasonable suspicion that linolenic acid enhances my POIS. I have other problems with zinc that may be not directly related to POIS. I had some reaction to green tea, but I don't exactly remember what and I have to retest it before I can say any more. Riboflavin is also known as vitamin B2, but I haven't tested that separately, so I am not sure.

AMPA receptors play a key role in the generation and spread of epileptic seizures.
It is true that I took Rivotril (Clonazepam) for years, but I have never had any kind of seizures in my life, so it is unlikely that AMPA is up-regulated in my case. Clonazepam is also used to treat epilepsy if someone hasn't heard about benzos.

The substances resulting from glucuronidation are known as glucuronides (or glucuronosides) and are typically much more water-soluble than the non-glucuronic acid-containing substances from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces (via bile from the liver).
Phenobarbital is an inducer of glucuronidation of both morphine and bilirubin.
Clonazepam is an inhibitor of morphine glucuronidation.
A low dose of phenobarbital may be beneficial for me as I probably have problems with both morphine and bilirubin.

Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in people with Crigler–Najjar syndrome, type II, or in patients with Gilbert's syndrome.
It is true that the only consistently bad blood parameter I have is an increased total bilirubin, however its value is only slightly increased. I also haven't experienced typical jaundice. There might had been some rare occasion when I had some slight yellowing of the conjunctiva, but usually it is only bloodshot and nothing else.

An elevated bilirubin level also seems to be a risk factor in COVID-19 infection, even though the infection wasn't very serious for me. Based on research bilirubin actually protects the virus against the antibodies.

FAAH inhibition can affect GABA.
A selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses.
Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity.
The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions.
Constitutively active receptor: A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist.

Niacinamide is a PPARA agonist just like PEA.
Panthenol is known to improve epidermal differentiation and to be an effective anti?inflammatory agent. In these studies we demonstrated the effects of panthenol on reducing PGE2 levels and tissue damage induced by a strong inflammatory cocktail in an in vitro model. This is relevant to the clinical setting as PGE2 is known to be elevated in subjects with sensitive skin. PEA also proved effective at reducing the levels of PGE2 and IL?6 in vitro, both of which are UV?induced inflammatory biomarkers. In addition, PEA reduced the levels of thymic stromal lymphopoietin (TSLP), an inflammatory and pruritogenic biomarker, consistent with its reported itch?relief activity. PEA is also a putative PPARA agonist that may mitigate irritation via this mechanism also.
Niacinamide (NAM) was shown to enhance the expression of epidermal differentiation genes and increase cellular NAD.
The former result is contradictory to that of Blander et al. and may reflect different testing methods, but the latter result is consistent with Rovito. Moreover, topical NADH, the reduced form of beta?nicotinamide adenine dinucleotide, is reported to be effective in the treatment of rosacea and contact dermatitis. Furthermore, the current work also demonstrated NAM?induced PPARA gene expression which is known to play an important role in regulating epidermal differentiation and reducing UV?induced erythema. Although speculative at this stage, it is likely that NAM may synergise with PEA in this mechanism.

PEA was first isolated from soy lecithin, egg yolk, and peanut meal.
One way in which PEA can indirectly activate CB1 and CB2 receptors is by inhibiting the expression of fatty acid amide hydrolase (FAAH), an enzyme that degrades the CB1 agonist AEA. The transient receptor potential vanilloid receptor type 1 (TRPV1) channels, which are also endocannabinoid targets, can also be indirectly activated by PEA. From these activities, it can be surmised that PEA needs synergistic actions among several mechanisms for it to be able to produce its effects.
I took a soy lecithin supplement a few years ago and I think it helped a little at the time, so I will need to test it again.

Intracellular NAD+ (nicotinamide adenine dinucleotide) concentrations reflect a balance between biosynthesis from discrete dietary precursors and "consumption" by enzymes that cleave NAD+ to release nicotinamide. Stressors such as ischemia have been known to induce NAD+ consuming enzymes such as poly-ADP-ribose polymerases and CD38; induction of these enzymes lowers NAD+. Tran and colleagues recently reported that renal tubular cell NAD+ levels are suppressed in models of acute kidney injury (AKI) and that this reduction of NAD+ may blunt fatty acid oxidation, reduce adenosine triphosphate generation, and elevate susceptibility to AKI stressors. Unexpectedly, they found that the stress-related fall in NAD+ was not only a consequence of increased consumption but also the result of decreased biosynthesis. In seeking a mechanism of decreased NAD+ biosynthesis, this study identified a novel function of the mitochondrial biogenesis regulator PPAR-gamma-coactivator-1alpha (PGC1a) to coordinately induce the enzymes that sequentially convert the amino acid tryptophan to NAD+. This series of enzymes is collectively referred to as the "de novo" or "kynurenine" (one of the intermediates between tryptophan and NAD+) biosynthesis pathway for NAD+. This study showed that renal tubular PGC1a expression defends the nephron against unrelated stressors, and that artificial augmentation of NAD+ could effectively mimic PGC1a's salutary effects in the tubule. Hence, a common PGC1a-NAD+ "axis" was described for kidney protection across rodent models of ischemia, inflammation, and nephrotoxicity.
The authors then embarked on a clinical trial to augment NAD+ among high-risk patients. Since the de novo pathway appeared to be blocked by QPRT suppression, they chose to administer nicotinamide (also referred to as niacinamide), the base version of vitamin B3, which the team had shown to boost renal NAD+ through another biosynthetic route known as the "salvage" pathway.

This article greatly proves what Prospero said, although I still need to confirm it in my case.
Specifically, we focus on the function of the peroxisome proliferator–activated receptor (PPARA), a target for PEA, which is best known for its role in reducing inflammation by decreasing cytokines, pro-inflammatory enzymes and oxidative stress. For this, PPARA agonists act as neuroprotectants in various neurological disorders like Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia. However, recent literature in the field suggest that PPARA has emerged as a new target that is useful as a novel approach to treat mood disorders by engaging neurosteroid biosynthesis.
PPARA activation has been shown as a natural response to stress, having the ability to mediate and modulate the stress response. In healthy adults, PEA, an endogenous PPARA agonist, significantly increase after clinical stress tests, corresponding with increased cortisol levels. PEA levels increase when healthy individuals experience pain or a depressed mood transiently. However, the levels of PEA in PTSD are low, suggesting a significant role in emotion regulation. As such, endogenous and synthetic PPARA ligands have predictably and successfully stabilized emotions in preclinical models.
Given that allopregnanolone directly binds this receptor, a reduction of allopregnanolone levels correlate to reduced GABA(A) receptor activity and dysfunctional behavior.
Intriguingly, the allopregnanolone level in the blood and CSF are reduced in patients of major depressive disorder (MDD), impulsive aggression, premenstrual dysphoric disorder, PTSD and other disorders of mood and emotions.
As a specific example, the allopregnanolone level in the CSF of female PTSD patients were 40% lower than in controls, and the allopregnanolone/dehydroepiandrosterone (DHEA) ratio negatively correlates with PTSD re-experiencing. To this end, studies are being pursued to verify lower levels of allopregnanolone during pregnancy as a predictor of postpartum depression (PPD).
Early studies have shown that allopregnanolone levels in the brain increase to levels that can activate the GABA receptors, during acute stressful events. Subsequently, it has been further hypothesized that the enhancement of GABAergic transmission decreases HPA activity and contributes to the behavioral stress response. Protracted stress, on the other hand, downregulates allopregnanolone biosynthesis. The decrease of allopregnanolone was the result of reduced levels of 5a-reductase type I mRNA and protein following social isolation. Hence, these findings suggest that allopregnanolone, its precursors, and analogs of allopregnanolone are suitable treatments for emotional regulation. For example, exogenous allopregnanolone attenuated the contextual fear response in a dose-dependent manner. In a similar murine social isolation model of PTSD, researchers showed that allopregnanolone treatment normalized HPA responsiveness and interrupted depressive- and anxiety-like behavior, which are hallmarks of clinical PTSD.
The summaries above suggest that the role of allopregnanolone in the progression and recovery of psychiatric disorders is similar to the emerging role of PPARA. Importantly, these similarities are not limited to their function in emotion regulation. Comparable actions of PPARA and allopregnanolone have also been observed across cognition, neurogenesis, neuroinflammation, neurodegeneration, and substance use disorder. Raso et al. suggest that the PPARA and allopregnanolone are different substrates of the same mechanism, whereby PEA-induced activation of PPARA regulates the biogenesis of allopregnanolone in astrocytes. To this end, when astrocytes were treated with PEA in vitro, an increased expression of enzymes that are crucial to allopregnanolone biosynthesis [steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc)] were reported along with increased cytoplasmic concentrations of allopregnanolone. This interdependent relationship between PPARA and allopregnanolone has also been alluded to in studies of pain perception. In studies of acute and persistent pain, researchers showed that the usual anti-nociceptive activity of PEA was reduced when activity of enzyme 5a-reductase and P450scc were blocked. PEA restored enzyme expression and increased allopregnanolone level in the spinal cord. Further support for this relationship was shown when PEA was used as neuroprotector and regulator of the pentobarbital-evoked hypnotic effect. In this case, PEA increased the expression of relevant enzymes and allopregnanolone concentrations in the spinal cord.
These findings suggest that allopregnanolone functions downstream of PPARA to mediate its therapeutic effects, thus, we further hypothesize that part of the mechanism of action of PPARA includes an upregulation of the biosynthesis of neurosteroids, by upregulating the expression of crucial neurosteroidogenic enzymes. A recent study by Locci and Pinna further demonstrated the allopregnanolone-dependent effect of PPARA-activation. In this study, a single dose of a PPARA agonist, PEA or GW7647, normalized the levels of allopregnanolone in socially isolated mice, improved depressive-like and anxiolytic-like behavior, and facilitated impaired extinction of fear memory. The therapeutic-like effects of the PPARA agonists were however obstructed by genetic ablation of PPARA, antagonism of PPARA, and inhibition of neurosteroidogenic enzymes. This and previous studies further support a possible PPARA-allopregnanolone biomarker axis in PTSD, and a new therapeutic target for emotional disorders.
Given the new relationship pointed out in this opinion article, the biochemical profile of PTSD may include a PPAR–allopregnanolone biochemical axis such that subpopulations of PTSD patients may display reduced allopregnanolone levels that can be increased by PPARA activation, only in allopregnanolone-deficient patients. Other components of the profile can also include changes in GABA(A) receptor subunit expression, decreased levels of endogenous fatty acid amides such as PEA and OEA, or downregulated expression of PPARA.

Another great article about the PPAR-neurosteroid axis that also lists great PPAR modulator nutrients.
In the pathogenesis of mood disorders, including major depressive disorder (MDD) and postpartum depression (PPD), both neuroinflammation and glutamate-mediated excitotoxicity mechanisms (neuronal death through glutamate-based over-activated stimulation) have been suggested to play a key role.
Interestingly, allopregnanolone reduces calcium influx through the activation of GABA(A) receptors expressed on cerebrocortical nerve terminals leading to decreased glutamate release and glial activation, supporting neuroprotective effects.
Locally produced allopregnanolone is responsible for the fine-tuning of GABA(A) receptors in corticolimbic glutamatergic neurons, a mechanism that has been linked with improvement of behavioral dysfunction. At this level, allopregnanolone may conceivably dampen neuroinflammatory processes following activation of glial-type GABA(A) receptors. Recent evidence shows allopregnanolone, following activation of a2-containing GABA(A) receptors and subsequent inhibition of toll-like receptor 4, can regulate the immune response by inhibiting proinflammatory processes.
Endogenously produced allopregnanolone plays a neurophysiological role in the fine-tuning of the GABA(A) receptors to GABAmimetics, positive allosteric modulators, and GABA agonists.
By this mechanism, allopregnanolone also regulates emotional behavior and stress-responses.
Moreover, decreased allopregnanolone levels in the postpartum period is associated with increased inflammation likely by activated microglia, which releases pro-inflammatory biomarkers, such as IL-1, IL-6 and TNF-a via the NFkB pathway that is also regulated by PPAR. Another mechanism involves the toll-like receptor 4 (TLR4), which, once activated by different triggers such as lipopolysaccharide (LPS), pathogen-associated molecular patterns (PAMPs), alcohol, stress or decreased levels of pregnenolone, forms a complex with intracellular co-activators, such as TIR Domain-Containing Adaptor Protein (TIRAP) and TRIF-related Adaptor Molecule (TRAM) to initiate a pro-inflammatory cascade that leads to NFkB activation and pro-inflammatory cytokines release. Low levels of allopregnanolone lead to increased calcium channel activity in activated nerve terminals and increased release of glutamate that facilitates excitotoxicity mechanisms. Unhealthy diets, including high fatty diets or alcohol abuse play deleterious effects on PPAR function that fails to regulate pro-inflammatory processes and greatly contribute to the neuroinflammation mechanisms underlying the pathogenesis of major depression and, possibly, PPD.
At the same time, increased allopregnanolone levels in neurons may stimulate brain derived neurotropic factor (BDNF) and exert important neuroprotective functions. We suggest that healthy diets enriched in micronutrients that are PPAR-agonists by enhancing the PPAR-allopregnanolone axis and decreasing inflammation may offer an alternative strategy to pharmacological treatments to prevent and safely treat mood disorders, including PPD.
Brexanolone, despite its proven high efficacy, showed adverse effects such as headache, dizziness, somnolence, and, in some cases, excessive sedation, which may complicate the safety of its use.
Together with PPARG, PPARA is deeply involved in several physiological and pathological conditions, including regulation of mitochondrial and proteasomal function, neuroinflammation, oxidative stress and neurodegeneration, which are considered key pathogenetic mechanisms involved in stress-related disorders, including anxiety and depression.
Intriguingly, PPAR mediates anti-inflammatory responses under several pathophysiological conditions and can stimulate biosynthesis of neurosteroids, such as allopregnanolone, with documented anti-inflammatory actions and role in improving mood symptoms, which suggests that the PPAR-neurosteroid axis may have a pivotal function in the modulation of mood by regulating inflammatory processes.
Intriguingly, PPARA activation stimulates the biosynthesis of allopregnanolone that in addition to elevating mood, has also been associated with an anti-inflammatory effect. Indeed, allopregnanolone binds at GABA(A) receptors expressed both on microglia and astrocytes and in glutamatergic pyramidal neurons, and it mediates anti-inflmmatory effects through blocking toll-like receptor 4. This results in NFkB inhibition.
Allopregnanolone's binding at GABA(A) receptors on monocytoid cells leads to diminished production of inflammatory mediators by these cells. Further, GABA suppresses astrocytes and microglia inflammatory responses to lipopolysaccharide (LPS) and INF-g by inhibiting the NFkB activation pathway and P38 MAP kinase. This process leads to a decreased release of pro-inflammatory cytokines, such as TNF-a and IL-6 and results in an attenuation of neurotoxicity in vitro. Interesting, similar anti-inflammatory effects were observed following the administration of the GABA(A) receptor agonist, muscimol and the GABA(B) receptor agonist, baclofen, suggesting the direct role of both types of GABA receptors in reducing neuroinflammation. Interestingly, GABA(A) receptors are also expressed in macrophages and lymphocytes T cells and their activation produces anti-inflammatory effects. In addition, neuroinflammation-associated release of glutamate from activated microglia has been implicated in the progression of neurodegenerative diseases, including Alzheimer's and Parkinson's disease and recent studies have shown that PPARs can modulate neurotoxicity by inhibiting glutamate release in LPS-activated microglia.
In vitro and in vivo studies show that 17B-estradiol, progesterone, and allopregnanolone reduce microglial-mediated inflammation.
A combined therapy of pioglitazone with the SSRI antidepressant, citalopram, showed a higher pharmacological response and remission rate, and rapid onset compared to citalopram alone. In another study, a 12-week pioglitazone administration induced antidepressant effects in patients with comorbid insulin resistance, supporting a link between depression and metabolic dysregulation.
Green tea, broccoli, onions, and berries are enriched in phytonutrients, such as carotenoids, ellagic acid, flavonoids, resveratrol, glucosinolates, and phytoestrogens that help fighting oxidation and inflammation. Naringenin, quercetin, hydrocaffeic acid, procyanidins, and anthocyanidins belong to the class of flavonoids and exert anti-inflammatory effects in vivo and in vitro by inhibiting the expression of iNOS, ICAM-1, MCP-1, COX-2, TNF-a, IL-1B and IL-6 expression.
PEA is abundant in egg yolk, soy oil, peanut oil, and corn, peas and beans, tomatoes and potatoes.
In addition, zinc modulates PPARG signaling, which is impaired in zinc deficiency.
In rodents, for instance, high-fat diets alter PPAR pathway causing abnormalities in the microbiome that can be reversed by rosiglitazone, a PPARG agonist. Several natural bioactive compounds act on PPARs, including the tea plant, soybeans, palm oil, ginger, grapes and wine as well as a number of culinary herbs and spices (e.g. Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris).
Curcumin has also shown anti-inflammatory and antioxidant effects by increasing PPARG activity.
OEA, which is a natural metabolite of oleic acid, and an endogenous PPARA modulator, shows anti-inflammatory activity. Then, foods rich in oleic acid, such as olive oil, avocado and almond oil can be used as part of the anti-inflammatory dietary patterns.
In addition, omega-3 (or n-3) PUFAs and their metabolites are natural ligands for PPARG.
EPA and DHA supplementation have been shown to decrease levels of key inflammatory cytokines TNF-a, IL-1B, IL-6, and IL-8.

Dietary flavonoids found in fruits and vegetables exert anti-inflammatory effects, as well by suppressing microglia activation through the PPARG mediated pathway.
Resveratrol, which is present at high levels in red grapes, nuts, and pomegranates, exerts metabolic, antioxidant, and anti-inflammatory activities, as well as neuroprotective effects through PPAR-activation. Similarly, quercetin induced antidepressant-like effect in the unpredictable chronic mild stress animal model of depression and induces antioxidant, anti-inflammatory activities, reduces excitotoxicity and augments 5-HT levels, linking the role of inflammation to depression. Foods rich in quercetin are capers, goji berries, onions, asparagus, spinach and red grapes. Resveratrol and quercetin are polyphenolic compounds that improve metabolic syndrome by altering PPAR expression. PEA shows antidepressant effects by binding at its main target, PPARA, and may increase endogenous levels of the endocannabinoids, anandamide (AEA) and 2-arachinoylglycerol (2-AG) and exert anti-inflammatory, analgesic, and neuroprotective properties.
We propose that PPAR might work in synergism with stimulation of neurosteroid biosynthesis to exert their beneficial effects by decreasing inflammation and relieving mood symptoms. Intriguingly, PEA-induced PPARA activation engages allopregnanolone levels in frontal cortex, hippocampus and amygdala to improve behavioral abnormalities in an animal model of stress-induced mood disorders
Moreover, allopregnanolone is also involved in BDNF expression and neurogenesis. In socially isolated mice reduced levels of allopregnanolone in corticolimbic areas are associated with BDNF deficiency, reduced neurogenesis and depressive- and anxiety-like behavior, supporting a multifunctional role of allopregnanolone for depression and anxiety prevention.
Intriguingly, studies have suggested that PPARA activation by administering synthetic PPARA agonists, including fenofibrate, is associated with stimulation of BDNF signaling cascade and improvement of behavioral dysfunction.
Moreover, FDA-approved synthetic PPARA agonists, including the fibrates (e.g., fenofibrate, clofibrate), prescribed for the treatment of hypercholesterolemia, could be repurposed to treat mood disorders by targeting the PPAR-allopregnanolone axis.

Table 1. contains a list of Functional Foods rich in micronutrients that activate PPARA and PPARG and induce pharmacological effects!

I think PPARA agonists may help me, so I will have to thoroughly test them. A short list of PPARA agonists: PEA (soy lecithin, egg yolk, and peanut meal) niacinamide, oleic acid (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).
Title: Re: FAAH Inhibitors
Post by: Prospero on May 02, 2021, 05:43:32 AM
To be precise, as I wrote you, it's not *my* argument, but someone else wrote this to me (as an hypothesis) and it made me think about what you were researching. I don't know if there is such a connection, it exceeds greatly my own competence.
Whatever, thank you for your findings on this topic.
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 02, 2021, 11:50:51 AM
To be precise, as I wrote you, it's not *my* argument, but someone else wrote this to me (as an hypothesis) and it made me think about what you were researching. I don't know if there is such a connection, it exceeds greatly my own competence.
Whatever, thank you for your findings on this topic.

The message I wanted to convey is that the theory is definitely valid as even official researchers proposed it. However as of this moment I can't clearly prove or refute it based on my personal experience and that is why I highlighted possible ways to modulate the process and check it against reality. Refuting it for one case doesn't necessarily mean that it is not true for at least some POIS cases.  At least PPARA agonists seem highly worthy to trial as many of them worked for one or another POISer. If someone has about the same experience with all of them then it is an indirect evidence for PPARA involvement in their personal POIS case be it either up- or down-regulation.
Title: Re: FAAH Inhibitors
Post by: Prospero on May 02, 2021, 05:28:30 PM
Yes, I understand very well, I just wanted to make this clarification because, considering my absence of skills, members of the forum may be surprised by the assertive tone of the quote, which is not from me.
As for the specific link with bilirubin, I have still some difficulty to clarify the relation between low glucuronidation (of 3adiol) and 5a-reductase inhibition.
I also noticed that I had rather bad reactions to zinc and green tea (worsening of some of my usual Pois symptoms, notably tachycardia) but it may have nothing to do with 5a-reductase.
Lemon balm seems beneficient for me too, for my nervous symptoms. As for GABA as a supplement, some people seem to think that it can be transformed into glutamate and is not necessarily useful as a GABA receptor agonist.
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 04, 2021, 03:44:24 PM
The combination of lungwort tea and saffron is quite extraordinary. Unfortunately even this can't completely overcome POIS, but this is the best thing I have found so far. It reduces all aspects of POIS considerably. It is definitely a profound painkiller. It feels like most of my pain receptors are blocked. I can only imagine that a very high anandamide level desensitizes TRPV1 receptors. I can hardly feel the thighs and my dick feels like a limp mass. Well it probably shouldn't be used if someone actually wants to do sex, but it is a superb after-event treatment nonetheless. If any POISer doesn't have any positive reaction to this I can't imagine their case has anything to do with the endocannabinoid system or with FAAH inhibitors at least.

Random googlings because somewhere in forum it was mentioned that acetylcholinesterase inhibiton (and choline supplementation?) helps, someone with more science knowledge please confirm if relevant:

Pulmonariae officinalis (Lungwort) (Apparantely there are multiple lungworts, so NOT Lobaria pulmonaria)
The P. officinalis extracts showed slightly lower acetylcholinesterase inhibitory effects – 87.7%, tyrosinase inhibitory effects – 73.69%,

Saffron extract showed moderate AChE inhibitory activity (up to 30%),

I wonder about the chest pain you describe. I never have chest pain. Maybe the tea fixed something there for you if it claims it's for chest infections. Also claims it's for urinary tract infections

When reading Amazon reviews for teas with Lungwort, they say it really helped their breathing.
And in the forum here we sometimes discuss about breathing techniques or autonomic nervous system... hmmm very interesting.

Thank you for bringing this to my attention!
Actually I have been wondering about the possible role of acetylcholinesterase as well. However as of this moment I am almost completely sure about the beneficial involvement of FAAH inhibitors as it turns out that Echinacea also has FAAH inhibitory property. A possible explanation could be that acetylcholinesterase inhibition is also beneficial. There is a wide variance in the effective time of the advantageous compounds and saffron and lungwort seems somewhat distinct in that they take effect in a very short time. Of course this is a mere guess and more acetylcholinesterase inhibitory supplement and maybe even some prescribed medication have to be trialed before a clearer resolution can be made. It would be really lucky if someone who already had a positive experience with acetylcholinesterase inhibitors could test saffron or lungwort and could make a comparison.

I haven't read everything about lungwort (Pulmonaria officinalis), but it is good to know that it also contains Pyrrolizidine alkaloids (PA). However this is a bit worrying finding.
Pyrrolizidine alkaloids are produced by plants as a defense mechanism against insect herbivores.
Unsaturated pyrrolizidine alkaloids are hepatotoxic, that is, damaging to the liver. PAs also cause hepatic veno-occlusive disease and liver cancer. PAs are tumorigenic. Disease associated with consumption of PAs is known as pyrrolizidine alkaloidosis.
So even though it is filled with a lot of anti-cancerous compounds its excessive use could be detrimental in the long run. I still think it is a good choice for days when I want to have an O, but it doesn't seem like a good idea to use it on a daily basis.
Common centaury (Centarium umbellatum) is also available here, so I will surely try and see how it works.
Tussilago farfara, commonly known as coltsfoot is also used to treat asthmatic and flu symptoms, so I thought it would be interesting to see what it does. Unfortunately coltsfoot contains the most toxic and carcinogenic pyrrolizidine alkaloids, so it is definitely not for someone with a Gilbert's disease. Although experts have bred a variety that practically contains no detectable pyrrolizidine alkaloids.
Tussilago farfara leaves have been used in traditional Austrian medicine internally (as tea or syrup) or externally (directly applied) for treatment of disorders of the respiratory tract, skin, locomotor system, viral infections, flu, colds, fever, rheumatism and gout.
Tussilago farfara contains tumorigenic pyrrolizidine alkaloids. Senecionine and senkirkine, present in coltsfoot, have the highest mutagenetic activity of any pyrrolozidine alkaloid. In response, the German government banned the sale of coltsfoot. Clonal plants of coltsfoot free of pyrrolizidine alkaloids were then developed in Austria and Germany. This has resulted in the development of the registered variety Tussilago farfara 'Wien', which has no detectable levels of these alkaloids.

A pharmacy also sells coltsfoot here, but unfortunately not the 'Wien' variety.
I hope they soon realize that they should breed a low pyrrolizidine variety of Pulmonaria officinalis as well, as it is a truly wonderful medicinal plant otherwise.

About the chest inflammation: I am quite sure it has something to do with the lymph vessels and nodes. My chest is completely normal in appearance and I don't have any gynecomastia. After reading about mast cell activation here I wondered if it could be related. I don't frequently check it, but sometimes it seems like only minutes pass when the nodules are almost nonexistent and when hard nodules can be felt. Even when the nodules are solid they are hardly painful and they only sometimes get really inflamed. It is clear that it can't be cancer as it wouldn't appear and disappear in this way. It is also hard to believe that it is due to an infection as there is no excessive nasal pus production and the change couldn't be so rapid in such a case. The pain can develop minutes after or sometimes even before O, which is not sensible if we consider bacteria. They are still living organisms and can't proliferate this rapidly. Certainly I can't deny the possibility of some opportunistic pathogens, but then again what would be the reason they become opportunistic while in a chronic phase they are merely a nuisance.
I really think it is due to the excessive release of the capsaicin-like compound that gets there through the blood stream and for some reason this is the primary place where it clogs the lymph vessels. Fresh air is clearly beneficial when I have such a case, but that only can't resolve it on its own. If I do extended physical work outdoors it can actually become worse, so exertion is a more important factor than fresh air. In some severe cases I can feel the stabbing pain even in my back, so the lung may be at least partially involved, although radiography in one moderate case proved negative. There were several cases when I felt like I was dying, but still nobody believed that I had any problems and claimed it was all in my head. I don't even mention it anymore I just try to get through it somehow, but it is quite difficult when I have to work in such a state and also pretend that everything is alright.
The best term I found about lymph clogging is hypoperfusion of the lymphatic vessels, although without any apparent skin problems and the exact process is still a mystery.
It very rarely hurts at the sternum, but there are usually some slight red dots that are connected to acute POIS. I read it somewhere (probably on the site) that it is probably connected to histamine release and mast cell activation. Around 2009 I had a case when the site of the thymus gland was really inflamed for a few days, but this hasn't occurred since then. I didn't go to the doctor at the time as they wouldn't have believed me anyway due to the POIS controversy. The enlarged nodules are one of the best indicators of my actual POIS state besides the burning pain. They are followed by bloodshot eyes and then depression by the way.

A longer list of PPARA agonists (they can be found in this thread): fluoxetine, mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, cardamom (limonene and kaempferol), Tribu Saponin from Tribulus terrestris, AEA, OEA, and PEA, rosmarinic acid and biochanin A, PEA (soy lecithin, egg yolk, and peanut meal), niacinamide, oleic acid - OEA (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).
Of course I will try to find more and test as many as I can to see if there is a real connection.
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 11, 2021, 02:45:05 PM
I think acetylcholinesterase and tyrosinase inhibition may not lie at the core of my problems, but currently I also can't definitely rule it out. I tested common centaury (Centarium umbellatum), but it had no major effect on my POIS. It is true that it has a positive effect on POIS, but it is very weak compared to lungwort. To tell you the truth I couldn't drink more than 4 deciliter of its tea, as it has such a bitter and sour taste that its practically impossible to consume a greater amount. Nevertheless even a cup of lungwort tea has a very noticeable effect, so it is unlikely that the same mechanism is involved. In the previously mentioned study they used ethanolic extracts, but I am not sure if it could make such a big difference.

According to a native literature lungwort is the only exception in its family that doesn't contain PAs. Unfortunately I can't verify this, but at least I may not have to worry too much about possible adverse side-effects.

The extraction of new substances with AChEI activity from plants has been a very effective method to develop new anti-AD drugs. Galantamine is the only naturally occurring drug on the market, and it consists of alkaloids extracted from Amaryllidaceae. Huperzine A is also a common AChEI developed and marketed independently in China. Huperzine A can alleviate neuroinflammation and oxidative stress and improve cognitive function after repeated traumatic brain injury. Garcia et al. studied three Huperzia species and noted that Huperzia dichotoma could be a new source of Hup A, and Huperzia linifolia and Huperzia cuernavacensis were potential candidates from which to obtain additional anti cholinesterase compounds for the treatment of Alzheimer's disease. The traditional Chinese medicine Yinhuang oral liquid also has significant inhibitory activity against AChE. Zhang et al. identified the following potent AChEIs in Yinhuang oral liquid by using high-performance liquid chromatography-electrospray ionization mass spectrometry (ESI-MS): chlorogenic acid, cryptorchidic acid, baicalin, baicalein, etc. Among the plant extracts reported in other studies, an extract of T. chebula and the aerial part of Amygdalus scoparia (50% inhibition at 300 µg/mL) not only have acetylcholinesterase inhibitory activity but also have antioxidant activity. Palmatine, fluoroureone B, ginseng stem and leaf saponins (GSLS), two kinds of maleimides and macarubiginosin C, and the monoterpene latifolia have been proven to have AChE inhibitory activity and are all potential AChEI candidates.
Although BChE is considered to be a more effective target than AChE while hAChE and hBChE have 65% amino acid sequence homology, their overall structures are similar and the development of inhibitors for BChE still poses significant challenges. Carbamate cholinesterase inhibitors are good examples of drugs that are designed for the mechanism of BChE. Physostigmine and rivastigmine have been shown to have dual inhibitory effects on cholinesterases and are more selective to BChE than AChE.
In addition, (-)-pterin N, coumestrol, and the citrus flavanone hesperidin are all multifunctional inhibitors that have been extracted from nature, showing good inhibition against BACE1, AChE and BchE.
In addition to the dual effect cholinesterase inhibition properties, the leaves of Elatostema papillosum (EPL), Polygonum multiflortan and Spatholobus suberectus also exhibit potent antioxidant activity.
A number of new and effective BChE inhibitors have also been screened from natural products. Dihydroxanthyletin-type coumarins and pteryxin are both coumarin derivatives from plants. Cassia tora and Morinda officinalis are mature medicinal plants. Recent studies have shown that the extracts of both Cassia tora and Morinda officinalis can effectively inhibit the activity of cholinesterase. Through ITC analysis, Budryn et al. found that active substances in coffee, ferulic acid and dihydrocaffeic acid, could interact strongly with BChE, indicating the potential therapeutic effects of coffee.

Echinacea is a FAAH inhibitor!
Fatty acid amide hydrolase inhibition ranged from 34–80% among E. angustifolia genotypes and from 33–87% among E. purpurea genotypes. Simple linear regression revealed the caffeic acid derivatives caftaric acid and cichoric acid, and the alkylamide dodeca-2E,4Z-diene-8,10-diynioc acid 2-methylbutylamide, as the strongest determinants of inhibition in E. purpurea (r*=0.53, 0.45, and 0.20, respectively) while in E. angustifolia, only CADs were significantly associated with activity, most notably echinacoside (r*=0.26). Regression analysis using compound groups generated by hierarchical clustering similarly indicated that caffeic acid derivatives contributed more than alkylamides to in vitro activity. The results suggest that several phytochemicals may contribute to Echinacea's cannabimimetic activity and that ample variation in genotypes exists for selection of high-activity germplasm in breeding programs.

Unsaturated N-alkylamide lipids, the main constituent of E. purpurea and E. angustifolia preparations capable of activating the cannabinoid receptor type-2 (CB2) have been suggested to play a role as potential anti-inflammatory and immune-modulatory principles.
Here we show that ethanolic E. purpurea radix and herba extracts produce synergistic pharmacological effects on the endocannabinoid system in vitro. Superadditive action of N-alkylamide combinations was seen at the level of intracellular calcium release as a function of CB2 receptor activation. Likewise, synergism of the radix and herba tinctures was observed in experiments measuring LPS-stimulated cytokine expression from human PBMCs. While the expression of the anti-inflammatory cytokine IL-10 was significantly superstimulated, the expression of the pro-inflammatory TNF-a protein was inhibited more strongly upon combination of the extracts. We show that N-alkylamides act in concert and exert pleiotropic effects modulating the endocannabinoid system by simultaneously targeting the CB2 receptor, endocannabinoid transport and degradation.

I am sorry, but I mixed up Rhodiola Rosea and Hydratis canadensis earlier.
The common names for Rhodiola Rosea are arctic root, golden root or rose root, but not goldenseal.
Goldenseal (Hydrastis canadensis), also called orangeroot or yellow puccoon, is a perennial herb in the buttercup family Ranunculaceae, native to southeastern Canada and the eastern United States.
Note: Goldenseal is sometimes referred to as "Indian turmeric" or "curcuma", but should not be confused with turmeric.
Goldenseal contains the isoquinoline alkaloids hydrastine, berberine, berberastine, hydrastinine, tetrahydroberberastine, canadine and canalidine.
Goldenseal is harvested for its rhizomes because the concentrations of hydrastine and berberine in the shoots do not meet these requirements. Berberine and hydrastine act as quaternary bases and are poorly soluble in water but freely soluble in alcohol. The herb seems to have synergistic antibacterial activity over berberine in vitro, possibly as a result of efflux pump inhibitory activity.
Side effects: High doses may cause breathing problems, paralysis, and even death. Long-term use may lead to vitamin B deficiency, hallucinations, and delirium. In addition, goldenseal may cause brain damage to newborn babies if given directly or if taken by breastfeeding or pregnant mothers, and may affect blood pressure unpredictably because it contains several compounds that have opposite effects on blood pressure. A 2011 study found rats fed goldenseal constantly for two years had a greater tendency to develop tumors.
Goldenseal has been found to have inhibited cytochrome P450 CYP2D6, CYP3A4 and CYP3A5 activity by approximately 40%, a statistically and clinically significant reduction. CYP2D6 is a known metabolizer of many commonly used pharmaceuticals, such as antidepressants (including all SSRIs except for fluvoxamine), neuroleptics codeine and Metformin. Combining goldenseal with such medications should be done with caution and under the supervision of a doctor as it can lead to serious, perhaps fatal, toxicity.
There are several berberine-containing plants that can serve as useful alternatives, including Chinese coptis, yellowroot or Oregon grape root.

TRPV1 may underlie the pathophysiology of psychiatric and chronic pain conditions.
In this regard, potential links between TRPV1 and schizophrenia include dopaminergic mechanisms and cannabinoid mechanisms.
Deficits in pain sensation and altered vascular responsivity (flare response) to niacin have been reported in schizophrenic patients. Primary afferent fibres are the subset of primary afferent neurons involved in both pain and flare responses that are sensitive to capsaicin treatment, i.e. TRPV1-containing afferents. Thus, patients with schizophrenia might have an abnormality in capsaicin-sensitive primary afferent neurons. A reduced neuropil (neuron density pertaining to brain grey matter) count, which is seen in schizophrenic patients, might also be due to reduced synaptic density in cortical regions arising from deficits in input from capsaicin-sensitive peripheral neurons.
These findings suggest that neonatal capsaicin treatment may be useful for modelling aspects of schizophrenia.
The study also reported that cutaneous plasma extravasation responses to niacin and prostaglandin D 2 were reduced in capsaicin-treated rats. The neuroanatomical changes and reduced cutaneous plasma extravasation responses in capsaicin treated rats resemble those observed in schizophrenic patients and suggest a potential role for TRPV1 in this psychiatric disorder.
As previously highlighted, TRPV1 has been identified in the cortex, hippocampus, basal ganglia, cerebellum, olfactory bulb, mesencephalon and hindbrain. In rat brain slices, activation of TRPV1 by capsaicin increases the rate of firing of dopamine neurons of the midbrain ventral tegmental area in a concentration-dependent manner. Furthermore, in vivo experiments have shown that microinjection of capsaicin into the ventral tegmental area transiently increased dopamine release in the nucleus accumbens. Dopamine release by intraventral tegmental area administration of capsaicin was inhibited by the selective TRPV1 receptor antagonist, I-RTX, suggesting a role for mesencephalic TRPV1 in dopaminergic transmission. Regulation of dopaminergic signalling in the brain's reward circuitry implies that TRPV1 could represent an important target for schizophrenia, affective disorders and addiction.
Systemic administration of the selective endocannabinoid reuptake inhibitors AM404 and VDM11, or the FAAH and TRPV1 inhibitor AA-5-HT, attenuated spontaneous hyperlocomotion in dopamine transporter KO mice. These hypolocomotor effects were significantly attenuated by coadministration of the TRPV1 antagonist capsazepine, highlighting an important role for TRPV1 in these responses. Recently, cannabidiol, a nonpsychotropic plant cannabinoid known to desensitize TRPV1 in vitro in epileptiform activity, may have therapeutic potential in psychosis, but the mechanisms underlying that effect are not clear and recent studies hypothesize that TRPV1 might be involved alongside CB 1 receptors.
As such, alterations in the function of TRPV1 may underlie the pathophysiology of psychiatric and chronic pain conditions and their comorbidity.

The experiments confirm the existence of release-inhibitory CB1 receptors on cholinergic myenteric neurones. We conclude that anandamide inhibits the evoked acetylcholine release via stimulation of a receptor that is different from the CB1 and CB2 receptor. Furthermore, anandamide increases basal acetylcholine release via stimulation of vanilloid receptors located at primary afferent fibres. Stimulation of the vanilloid receptor by capsaicin causes an increase in basal acetylcholine release from myenteric neurons and smooth muscle contraction. These excitatory effects of capsaicin are inhibited by the combined blockade of NK1 and NK3 tachykinin receptors, which suggests that the stimulation of vanilloid receptors induces a release of tachykinins which, in turn, cause release of acetylcholine via activation of NK1 and NK3 receptors on cholinergic myenteric motoneurones.
The present study shows that the endocannabinoid anandamide has opposite effects on basal and evoked release of acetylcholine which are mediated by different mechanisms.
Anandamide increased basal acetylcholine release and muscle tension and this effect was competitively antagonized by capsazepine but not by CB1 or CB2 receptor antagonists.
Anandamide has previously been shown to decrease the twitch contraction of the myenteric plexus-longitudinal muscle preparation with an pEC50 value (5.05) which is similar to the present value (5.2). 
It is generally accepted that the cholinergic myenteric neurones have release-inhibiting CB1 receptors.
Several studies have shown that the potency of cannabinoid receptor antagonists is diminished if anandamide is used as an agonist.
Our data support this hypothesis and suggest that anandamide inhibits the electrically-evoked release of acetylcholine from cholinergic neurones innervating the longitudinal muscle via stimulation of a non-CB1 receptor that is susceptible to antagonism by SR141716A but with a lower KB value than that observed for this compound at the CB1 receptor.
It should be noted, though, that functional studies suggest that the cholinergic contraction of the circular muscle of the guinea-pig ileum is inhibited by anandamide acting at the CB1 receptor.
Anandamide increased basal acetylcholine release from the myenteric plexus-longitudinal muscle preparation via stimulation of vanilloid receptors. This effect involves the release of tachykinins from afferent nerves. In addition, anandamide inhibited the electrically-evoked release of acetylcholine and longitudinal muscle contraction. Likewise, the cannabinoid receptor agonist CP55940 decreased the evoked acetylcholine release and twitch contraction. The agonists differed, however, in that the CB1 receptor antagonist SR141716A was much less potent in blocking the inhibitory effect of anandamide than that of CP55940. We therefore conclude that anandamide inhibits the evoked acetylcholine release from guinea-pig myenteric neurones via a non-CB1 receptor.

The concentrations required for inhibition of FAAH are generally in the micromolar range, which is, by any standard, modest, particularly when compared either with the most potent FAAH inhibitors available, or with the potencies of the flavones toward oestrogen receptors.
The concentrations of kaempferol required to inhibit AEA hydrolysis in both homogenates and intact cells are similar to those required for antioxidant effects, inhibition of EGF-receptor intrinsic tyrosine kinase and PKC, inhibition of 20a-hydroxysteroid dehydrogenase, inhibition of interleukin-4-induced STAT6 activation and activation of COX-2. The nature of the compounds begs the question as to whether dietary flavonoid intake is sufficient to inhibit FAAH in vivo. At the outset, it should be pointed out that extrapolation of in vitro data, such as reported here, to the situation in man is difficult, to put it mildly, but 'ballpark' estimates can be considered. In plants, flavones are often, but not exclusively, present as glycosides, but aglycones are produced after ingestion. The two most potent (with respect to FAAH inhibition) compounds were 7-hydroxyflavone and 3,7-dihydroxyflavone, but these compounds, although naturally occurring (in Dracaena cochinchinensis, Clerodendron phlomoidis and Platymiscium praecox Mart., found in China, India and Brazil, respectively) cannot be described as commonly occurring compounds. The mean dietary intake of kaempferol by adults is ~5 mg/day, whereas that of quercetin is ~16 mg/day; intakes of apigenin, myricetin, fisetin and luteolin are much lower, although there is naturally a large inter-individual variation. Following intake of a bowl of endive soup, containing 8.65 mg of kaempferol equivalent, a mean peak plasma kaempferol concentration of ~0.1 um was found for eight healthy subjects. In another study, the plasma concentrations of kaempferol and quercetin following ingestion of concentrated black tea (providing 27 and 49 mg of these flavonoids, respectively) were found to be 15 and 29 ug/L, corresponding to ~0.05 and ~0.1 um, respectively. These values for kaempferol are considerably lower than the concentrations needed for inhibition of FAAH activity in either cell-free homogenates or intact cells, and suggests that inhibition of FAAH following ingestion of dietary flavonoids is unlikely.
A separate question is whether inhibition of FAAH contributes to the pharmacological actions of flavonoids in experimental animals. As an example, kaempferol and quercetin (administered orally at a dose of 50 mg/kg as glycosides) produce antinociceptive effects in a model of visceral pain (acetic acid writhing) and anti-inflammatory effects in a carrageenan model. Such effects are also seen with URB597, so it is at least theoretically possible that inhibition of peripheral FAAH can contribute to such actions.

These are classified into phenolic acids, flavonoids, stilbenes, coumarins, lignins, and tannins. Coumarins are found in a variety of plants such as tonka bean (Dipteryx odorata), sweet woodruff (Galium odoratum), sweet grass (Hierochloe odorata), deer-tongue (Dichanthelium clandestinum), vanilla grass (Anthoxanthum odoratum), mullein (Verbascum spp.), and sweet-clover (Melilotus sp.). Resveratrol, a stilbenoid present in many fresh fruits and plants such as Polygonum cuspidatum, Arachis hypogea, Cassia sp., Eucalyptus, Morus rubra, and Vitis vinifera, has been reported to have numerous biological properties, such as antioxidant, anti-inflammatory, anti-cancer, anti-aging, anti-obesity, anti-diabetes, cardioprotective and neuroprotective effects.
Fungal metabolites with clinical use include beta lactams, e.g., penicillins G and V, statins, cholesterol-lowering blockbuster drugs, the immunosuppressant cyclosporin and the anti-migraine ergotamine. Beta-lactams are the most widely used class of antibiotics that, with the discovery of penicillin, produced by the fungus Penicillium notatum, early in the twentieth century, marked a new era for the treatment of bacterial infections. Cyclosporin is employed for the treatment of autoimmune diseases such as psoriasis; it is a peptide isolated from Tolypocladium inflatum.

I took soy lecithin [1200 mg softgel] again and it seems to have a beneficial effect, although it is relatively weak. If I take two with only a few hours difference it may cause a weak cramping heartache as a side-effect.
Artichoke tea works relatively well. Drinking 1 liter seems to have a weak to moderate efficacy. It has no rapid action, only long term (6-12 hours) benefit.
Also alfalfa works like a charm, but more about this in my next post.
Title: Re: FAAH Inhibitors
Post by: berlin1984 on May 12, 2021, 12:27:48 PM
I have to say that Saffron (Affron©)  is the single best supplement I discovered in the last year. (thanks!)

It improves my orthostatic intolerance like feeling by a lot. I have less need to sit down with it. It also improves motivation/drive and improves the gut transit.

But I need to remember to take it consistently.
I stopped taking it for a while and took another supplement containing a bit of Saffron. On one day in the morning, I could barely keep standing, had to lie down again. Tried my other hacks (drinking more water, drinking alcohol free wheat beer, eating salty stuff) and they didn't work. Until I remembered the saffron. Took one dose and after half an hour I was completely fine again. I could stand, walk, didn't feel weak etc.

It's not perfect yet though.

Maybe I should try to combine it with Ashwagandha ( again which I stopped because after some weeks it leads to heart palpitations. Hm.
By the way, Ashwagandha extract inhibits acetylcholinesterase.
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 15, 2021, 05:32:18 AM
Lucerne which is also known as alfalfa surely works! The product I bought is called lucerne [500 mg per pill] containing powdered lucerne made with cold pressurized method without any additives. For the first time I took it I tested it right away against an O and amazingly it completely prevented POIS! I had practically no symptoms. No bloodshot eyes, no coldness, no fatigue or brain fog. On the next morning I couldn't feel any enlarged lymph nodes in the breasts and I had no muscle fatigue, although I wouldn't say it was full of energy. The stool was a bit harder than usual, but it was completely normal with no burning feeling at all. I had a really slight headache in the morning, but it passed on its own after a few hours. To be frank I think I used quite a high dose as the daily recommendation is 5 pills (2.5 g) and I took 8 pills (4.0 g or 4000 mg) on that day. I took three pills in the morning then about 8-10 hours later took another two. Two hours later I had an O and shortly after took another two. Before going to sleep I had another one. Lucerne doesn't seem to have a rapid effect onset, so it must have been important that I also took it in the morning. Of course I don't believe that it will keep working this well as the effectiveness of saffron and MACA also reduced after a short time, but it is still a very good product against my POIS.
Actually I realized that most of the stuff that work have a slow effect onset. They can ameliorate POIS if it occurs, but I think it is much better to also take them well beforehand as it is better to reduce POIS when it happens, so it won't upset the homeostasis to a greater extent. I haven't exactly figured out the exact values for most of the stuff and it may be difficult as well, but for most it is in the 6-12 hours range after their consumption. I think Echinacea works best if taken about 6 hours before an O, while alfalfa may be best taken about 10 hours beforehand. Many here claim that niacin or niacinamide works best when the flare response happens, but I don't think this can be applied to my case. I think I need to take it several hours before O to have the best effect. Of course I haven't confirmed this yet, but I will definitely need to. This may also mean that when combining different components their synergy may be more ideal if they are not taken at once, but also considering their peak efficacy.
Now the problem is that I don't know why lucerne/alfalfa worked so well. Earlier I proposed that alfalfa could be a potent FAAH inhibitor due to its daidzein content. What I can gather is that daidzein can be found in the root and the sprout, but I am not sure how much if any can be found in the plant itself. I also had problems with kudzu root which contains daidzein. Kudzu also contains puerarin which is probably (by a quick scholar check) an agonist of all PPARs (PPARpan), but I am not sure if it could be the reason why it didn't work. As a third possibility I wondered if another compound could be the reason. As alfalfa is high in phytoestrogens this seemed to be an interesting prospect. Searching about coumestrol something rather surprising and interesting information turned up. Coumestrol is actually a potent inhibitor of the AKR1C family which includes different hydroxysteroid dehydrogenases that are involved in the conversion of hormones with different affinities.
It turns out that many of the flavanoids previously mentioned have an inhibitory effect on these enzymes. This gives a brand new perspective to be explored, but it may not be easy to reach a definite conclusion without actual measurements.

Genistein and daidzein are phytoestrogens present in soybean seeds and flour, and the structurally similar coumestrol is found in alfalfa.
Phytoestrogens can bind to estrogen and other receptors in vitro and can exert estrogenic effects in vivo.
Genistein may also act through other mechanisms, including inhibition of enzymes (aromatase, tyrosine kinases, and DNA topisomerase), increased synthesis of sex hormone binding globulin and antioxidation.

Raw alfalfa seeds and sprouts are a source of the amino acid canavanine. Much of the canavanine is converted into other amino acids during germination so sprouts contain much less canavanine than unsprouted seeds. Canavanine competes with arginine, resulting in the synthesis of dysfunctional proteins. Raw unsprouted alfalfa has toxic effects in primates, including humans, which can result in lupus-like symptoms and other immunological diseases in susceptible individuals, and sprouts also produced these symptoms in at least some primates when fed a diet made of 40% alfalfa. Stopping consumption of alfalfa seeds can reverse the effects.
Alfalfa, like other leguminous crops, is a known source of phytoestrogens, including spinasterol, coumestrol, and coumestan. Because of this, grazing on alfalfa during breeding can cause reduced fertility in sheep and in dairy cattle if not effectively managed.

Isoflavonoids are secondary metabolites that can be divided into isoflavones and pterocarpans. Certain isoflavones found in red clover leaves include daidzein, genistein, pratensein and prunetin. Several in vitro, animals and human studies have shown isoflavones to have antidiabetic properties. The results of Gray and Flatt demonstrated the presence of anti-hyperglycemic, insulin-releasing and insulin-like activity in alfalfa. Despite insulin therapy, diabetic patients suffer from some chronic clinical complications due to high blood glucose which induces non-enzymatic glycosylation of natural proteins such as hemoglobin, lens proteins, biomembrane proteins, albumin, collagen and myelin.
Alfalfa has an antihyperglycemic property and insulin-releasing action that is known in both of animal and human studies. These activates of alfalfa extracts may be useful for type 2 diabetes and especially important for patients with "pre-diabetic" state for diabetes prevention.
They mentioned antioxidants can partially inhibit the formation of glycated hemoglobin by lowering the levels of lipid peroxides.
This suggests that the isoflavonoids inhibit hemoglobin glycosylation. Isoflavonoids could improve diabetes by inhibiting this reaction. These components exert beneficial effects on glycosylation of hemoglobin through their antioxidative actions, therefore, two used plant in this study containing isoflavonoid may be useful in minimizing glycation of hemoglobin.

There is a possibility that some of the hydroxysteroid dehydrogenases (HSDs) are overexpressed and this could lead to the accumulation of "inactive" hormones while depleting the active ones.
Phytoestrogens are plant-derived, non-steroidal constituents of our diets. Much less is known about their actions on the androgen and progesterone metabolizing enzymes. We have examined the inhibitory action of phytoestrogens on the key human progesterone-metabolizing enzyme, 20a-hydroxysteroid dehydrogenase (AKR1C1). This enzyme inactivates progesterone and the neuroactive 3a,5a-tetrahydroprogesterone (allopregnanolone), to form their less active counterparts, 20a-hydroxyprogesterone and 5a-pregnane-3a,20a-diol, respectively. The most potent inhibitors were 7-hydroxyflavone, 3,7-dihydroxyflavone and flavanone naringenin with IC50 values in the low uM range.
Phytoestrogens can act in different ways: they are agonists or antagonists of estrogen receptors (ERa and ERb), the pregnane X receptor and the constitutive androstane receptor. They have stimulatory effects on hepatic sex-hormone-binding globulin (SHBG), they inhibit tyrosine kinases, and thus prevent growth-factor-mediated stimulation of proliferation, and they can also modulate the activities of key enzymes in estrogen biosynthesis, such as aromatase, sulfatase, sulfotransferases, 3B-hydroxysteroid dehydrogenases (3B-HSDs) and 17B-hydroxysteroid dehydrogenases (17B-HSDs); in this manner, they may act at a pre-receptor level.

Cell-specific metabolic activation of inactive hormone precursors represents a novel level of hormonal regulation. Steroid hormones exist in active and inactive forms that can be enzymatically interconverted. The active forms have high affinities towards their corresponding receptors, while
the inactive forms have very low affinities. The enzymes that interconvert the active and inactive forms, and that thus act as molecular switches, are pre-receptor regulatory enzymes. Tissue-specific expression of these enzymes allows for the regulation of local concentrations of the active steroid hormones. These pre-receptor regulatory enzymes include different conjugating phase II enzymes,
cytochrome P450 enzymes and hydroxysteroid dehydrogenases (HSDs).
Four human HSDs, AKR1C1-AKR1C4 (hence members of the AKR1C subfamily), function in vitro as 3-keto, 17-keto and 20-ketosteroid reductases, or as 3a, 3B, 17B and 20a- hydroxysteroid oxidases, to varying degrees. These AKR1C isoenzymes are expressed in different tissues: AKR1C4 is liver specific, while AKR1C1-AKR1C3 are expressed ubiquitously, and have been detected at different levels in liver, lung, prostate, mammary gland, uterus, brain, small intestine, testis and other tissues. In intact cells, all of the AKR1C isozymes preferentially work as reductases, and can either form potent androgens (testosterone from androstenedione) and estrogens (estradiol from estrone), or convert the potent androgen 5a-dihydrotestosterone (5a-DHT) into the less potent 3a- or 3B-androstandiol, and the potent progesterone into its less active metabolite 20a-hydroxyprogesterone (20a-OHP). In this manner, many AKR1Cs regulate the occupancy and trans-activation of androgen, estrogen and progesterone receptors. AKR1Cs have important roles also in the production and inactivation of neuroactive allopregnanolone (3a,5a-tetrahydroprogesterone, 5a-THP), which allosterically modulates the activity of the gamma-aminobutyric acid (GABA)A receptor, and thus exhibits anesthetic, analgetic, anxiolytic and anticonvulsant effects. Among these AKR1C isoforms, AKR1C1 acts preferentially as a 20a-HSD and inactivates progesterone by its conversion to 20a-OHP, which has a low affinity for progesterone receptors; it also converts 5a-THP into 5a-pregnane-3a,20a-diol, which has a weak affinity for the (GABA)A receptor. AKR1C1 thus diminishes the levels of progesterone and 5a-THP in peripheral tissue. Among the steroid metabolizing enzymes, the inhibitory effects of phytoestrogens have been studied against aromatase, sulfatase, sulfotransferases, 5a-reductase, 3B-HSD d5/d4 isomerase, 11B-HSD type 1 and type 2, and 17B-HSD isoenzymes. Phytoestrogens have been shown to inhibit the human 17B-HSD types 1, 2, 3 and 5. There are, however, no reports of phytoestrogen inhibition of other human 17B-HSD isoforms (types 4, 7, 8, 10, 11, 12 or 13) or 20a-HSDs. We have focused our attention on AKR1C1, which is regarded as the dominant form of human 20a-HSD and has an important role in progesterone and 5a-THP inactivation. Thus it may be involved in the development of breast and endometrial cancers, as well as in conditions such as premenstrual syndrome, catamenial epilepsy and depressive disorders.
We next examined 25 compounds for inhibition of recombinant AKR1C1: 21 plant-derived estrogenic compounds (flavones, flavanones, isoflavones, coumestans, coumarin, stilben resveratrol and organic acids); one myco-estrogen (zearalenone); three synthetic estrogens/antiestrogens (diethylstilbestrol, equilin and tamoxifen).
The most potent inhibitors of 9,10-PQ reduction were 7-hydroxyflavone and 3,7-dihydroxyflavone, with IC50 values of 2.3 and 4.9 M, respectively. An additional hydroxyl group at position 5 decreased the inhibitory potential (5,7-dihydroxyflavone; 28% inhibition) and a flavone with one hydroxyl group at position 5 (5-hydroxyflavone) had no inhibitory effects. The replacement of the hydroxyl at the same position with a metoxyl group (5-metoxyflavone) enhanced the inhibition (33%). Of the other flavones, kaempferol (4,3,5,7-tetrahydroxyflavone) with hydroxyl groups at positions 3 and 7 was very potent (9.3 M IC50), quercetin (4,5,3,5,7-pentahydroxyflavone), with additional hydroxyl groups at position 5 was quite potent (60% inhibition; 26.8 M IC50) while luteolin (4,5,5,7-tetrahydroxyflavone; 44% inhibition) and apigenin (4,5,7-trihydroxyflavone; 19.8% inhibition), which both have only the 7-hydroxyl group, were less potent inhibitors. Also in flavanones the presence of hydroxyl groups increased the inhibitory effect and naringenin possessing hydroxyl groups at positions 4, 5 and 7 was a very potent inhibitor with IC50 value of 2.6M. Similar results were obtained for progesterone reduction. Our results thus show that the hydroxyl groups at positions 3 and 7 are important for efficient inhibition by flavones, while the hydroxyl groups at positions 4, 5 and 7 determine the inhibitory effect of flavanones.
The isoflavones genistein (4,5,7-trihydroxyisoflavone) and biochanin A (4-metoxy-5,7 dihydroxyisoflavone) were potent inhibitors of 9,10-PQ reduction, with IC50 values of 5.0
and 5.7M, respectively. The absence of the 5-hydroxyl group (4,7-dihydroxyisoflavone-daidzein) decreased the inhibitory activity (40% inhibition), indicating that for isoflavones, the hydroxyl groups at positions 5 and 7 are important for efficient inhibition of 9,10-PQ reduction. Interestingly, isoflavones had almost no inhibitory effects on the reduction of progesterone. Inhibition by genistein, biochanin A and daidzein was also tested in the spectrophotometric assay, which confirmed, as previously shown by TLC assay, that these compounds are not inhibitors of progesterone reduction.
Coumestrol and coumarin were less effective as inhibitors of 9,10-PQ reduction than of progesterone reduction. Stilben resveratrol was less potent inhibitor showing about 30% and 10% inhibiton of 9,10-PQ and P reduction, respectively. The plant organic acids glycyrrhetinic and abitinic acid were effective inhibitors of 9,10-PQ reduction, with IC50 values of 12.9 and 33.7 M, respectively. However, only glycyrrhetinic acid showed inhibitory action on progesterone reduction, again probably because of the different binding modes of 9,10-PQ and progesterone. The myco-estrogen zearalenone, which is contained in mould-infected food, showed about 40% inhibition of 9,10-PQ and progesterone reduction. As a comparison, for AKR1C3, IC50 values of 2 and 4M were reported for androstanediol oxidation and androstanedione reduction, respectively, at 30 nM substrate concentrations. Zearalenone has been reported to have no inhibitory action towards the reductive human 17-HSD type 1, a member of the SDR superfamily, while it has been shown to inhibit the oxidative human 11-HSD type 2, as well as the oxidative activity of human 11-HSD type 1 and fungal 17-HSD.
Tamoxifen has been reported previously to be a weak inhibitor of AKR1C3 and 17-HSD types 1 and 3, members of the SDR superfamily while diethylstilbestrol has also been shown to inhibit AKR1C3, but to have no effects on 17-HSD type 1. Equilin, a potent inhibitor of human 17-HSD type 1, showed 64% and 40% inhibition of AKR1C1, and IC50 values of 24 and 286 M for 9,10-PQ and progesterone reduction, respectively.
Usami et al. reported benzodiazepines, especially diazepam and medazepam, are efficient inhibitors of AKR1C1 and IC50 values in low micromolar range were determined when following oxidation of 1 mM S-tetralol. Later the same group found benzbromarone (BZB) and TBPP to be selective and more potent inhibitors with IC50 values in nM range.
Lately, Bauman et al. presented a group of non-steroidal anti-inflammatory drug (NSAID) analogs as inhibitors of AKR1C1, the best inhibitor of oxidation of 100M 1-acenaphthenol was 5-methyl-N-phenylantranilic acid with 3.2M IC50 and KI = 0.88M.
Also phytoestrogens revealed IC50 values in the low micromolar range. Lower substrate concentrations used in our enzyme assay (5 M 9,10-PQ) suggest phytoestrogens are less potent inhibitors than benzodiazepines, BZB, TBPP and NSAID analogs, however, one should take into account that an average individual is not constantly exposed to the later substances.
Of the AKR1C isozymes, phytoestrogens have already been tested as inhibitors of AKR1C3. The reduction of androstenedione to testosterone and oxidation of androstanediol to androsterone were studied. Since the AKR1C isoforms act as reductases in vivo, we focussed here on the inhibitors of reduction. The reduction of 30 nM androstenedione to testosterone was potently inhibited by zearalenone, coumestrol, quercetin and biochanin A, all with IC50 values below 15 M. For 7-hydroxyflavone, naringenin, 3,7-dihydroxyflavone, kaempferol, genistein, biochanin A and glycyrrhetinic acid, which are the best inhibitors of AKR1C1, these were not so effective on AKR1C3, with IC50 values 20M and above. Although 5-hydroxyflavone, tamoxifene and flavanone showed no inhibition of AKR1C1, they still had some inhibitory action on AKR1C3, with IC50 values above 20 M. Thus, despite an 87% identity of their amino acids, AKR1C1 and AKR1C3 show distinct structural requirements for potent inhibition.
AKR1C1 is expressed in the breast, uterus and other peripheral tissues, where it regulates progesterone action. Thus, its inhibition may have profound effects in these tissues. Recent findings suggest that P endogenously produced or exogenously administered does not affect the risk for breast cancer. The increase in breast cancer risk found in women receiving estrogen and progestin, compared with those receiving estrogen alone, may be explained by the fact that some progestins exert non-progesterone-like effects, such as androgenic, estrogenic or glucocorticoid. But also progesterone metabolites may influence proliferation of breast cells; higher levels of 5a-reduced progesterone metabolites and lower levels of d4-metabolites in tumor breast tissue suggest 5a-pregnanes (5a-P), acting through specific 5a-P receptors (5a-PR), stimulate cell proliferation, while 4-pregnanes (including 20a-OHP) down regulate expression of these receptors and have the opposite effect. Although loss of AKR1C1 expression has been reported in breast cancer, inhibition of AKR1C1 may still affect the ratio between progesterone and 20a-OHP, but this may have no effect on 5a-PR, but rather on the occupancy of PRAB and receptor mediated action of progesterone. In the uterus, inhibition of AKR1C1, which is upregulated in endometrial cancer, can result in a higher concentration of progesterone and may thus protect the endometrium from the mitotic activity of exogenous and endogenous estrogens. AKR1C1 is also important in the brain, where it regulates the action of neurosteroids.
Inhibition of AKR1C1 with phytoestrogens that readily pass across the blood–brain barrier could result in higher concentrations of the neuroactive 5a-THP (allopregnanolone), and may thus influence mood, memory, cognition, neuroendocrine and reproductive behaviors.
We have shown here that phytoestrogens inhibit recombinant AKR1C1. The most potent inhibitors of progesterone reduction revealed IC50 values in the low micromolar range. Phytoestrogens may thus affect the whole range of steroid metabolizing enzymes, and may in this manner influence not only estrogen and androgen action, but also progesterone action in peripheral tissues, such as in the breast and endometrium. In addition, phytoestrogens may also affect the synthesis and inactivation of neurosteroids, which are also catalyzed by the AKR1C isozymes.

Check out Table 1!

AKR1C3 was found to play a pivotal role in the synthesis of testosterone (T) and dihydrotestosterone (DHT), which are the most robust stimuli for activation of the growth, proliferation and metastasis of prostate cancer cells. In vitro experiments have shown that AKR1C3 is up-regulated in prostate cancer cells as a survival adaptation in response to T/DHT deprivation. The overexpression of AKR1C3 was found to increase the intracellular synthesis of testosterone from 4-androstene-3,17-dione in LNCaP cells and resulted in resistance to the 5a-reductase inhibitor finasteride.
Several studies have indicated that AKR1C3 overexpression increases with PCa progression through the mechanisms underlying the key steroidogenic enzyme AKR1C3, which possesses 17B-hydroxysteroid dehydrogenase type 5 (17B-HSD5) activity, and PGF synthesis enzyme.
During malignant transformation of prostatic epithelial cells, androgen regulation shifts from paracrine to autocrine and prostatic epithelial cells adaptively acquire the intratumoral androgen synthesis ability to maintain the growth of tumor cells. It is reported that AKR1C3 is a pivotal enzyme in converting d4-dione to testosterone, 5a-DHT to 3a-diol, and androstenedione and dehydroepiandrosterone (DHEA) to intraprostatic testosterone in the progression of PCa and CRPC. Some studies showed that AKR1C3 has a preference in prostate cancer for the androstenedione to DHT by an alternative pathway. Moreover, AKR1C3 possesses 11-ketoprostaglandin reductase activity and is capable of converting PGD2 to 9a, 11B-PGF2a, which promotes prostate cell proliferation through the PI3K/Akt signaling pathway in androgen receptor-negative PCa.

Phytoestrogens contained in a vegetarian diet are supposed to have beneficial effects on the development and progression of a variety of endocrine-related cancers. We have tested the effect of a variety of dietary phytoestrogens, especially flavonoids, on the activity of human 17B-hydroxysteroid dehydrogenase type 5 (17B-HSD 5), a key enzyme in the metabolism of estrogens and androgens.
Phytoestrogens are plant-derived, non-steroidal compounds possessing estrogenic activity. They can be divided into three main classes: flavonoids, coumestans and lignans.  The soybean is the main dietary source for isoflavones. Flavones and flavanones are widely distributed in all plant families and are found in fruits, vegetables, berries, herbs, beans, and green tea. High levels of coumestrol are found in alfalfa and various beans.
Multifunctionality is a special characteristic of human 17B-HSD 5 which enables conversion at the 3a-, 17B- and the 20a-position of estrogens, androgens as well as progestins. In humans, 17B-HSD type 5 is expressed in reproductive and hormone target tissues, e.g. in ovary, uterine endometrium, mammary gland, testis, and adrenal gland. Additionally, the enzyme has been detected in prostate indicating the possibility of local steroidogenesis from circulating inactive precursors. Substrate specificity of 17B-hHSD type 5 is comparable to 17B-HSD type 3 which catalyzes the conversion of androstenedione to testosterone. It also degrades the active androgen 5a-DHT to androstanediol and subsequently to androsterone in the prostate. Consequently it was suggested that the enzyme controls the occupancy of the androgen receptor and regulates local androgen concentration, which is instrumental for the control of normal and abnormal growth of the prostate.
Our experiments substantiate that a major part of the tested dietary hormones has inhibitory effects on both, the reductive and oxidative, activities of 17B-hHSD 5 analyzed here. Reduction of androstenedione to testosterone as well as oxidation of androstanediol to androsterone are affected. The most potent inhibitors are coumestrol, zearalenone, the flavone quercetin and the isoflavone biochanin A (the precursor of genistein). On the other hand, substances like the synthetic antiestrogen tamoxifen, the strong natural estrogens daidzein and coumarin had no influence on both types of reaction. 18B-glycyrrhetinic acid strongly inhibited the reduction of androstenedione but had no effect on the oxidative reaction.
Under reductive conditions a double bond in ring C, which is characteristic for flavones, increases the inhibitory strength (flavanone versus flavone, naringenin versus apigenin). In contrast, flavanones lacking the double bond have stronger influence on the oxidative activity of 17B-hHSD 5 (flavone vs flavanone, apigenin vs naringenin).
The most potent inhibitors are present in very common dietary products, with the exception of zearalenone, which is found in mold infected food. Quercetin (a flavone) is found in e.g. apples, onions, chamomile, and tea. Biochanin A (an isoflavone) as well as the strong inhibitor coumestrol are in a variety of beans, especially soybeans, a major component of the Asian diet. Consequently, high plasma values of isoflavones have been observed in Japanese man. The highest individual value exceeded 2 uM, compared to a mean plasma value for daidzein and genistein in Finnish subjects of about 5 nM each. These high local phytoestrogen levels might alter local steroid hormone concentration, e.g. by inhibiting 17B-hHSD 5, as shown in the present study.
The involvement of 17B-hHSD 5 inhibition in delay of breast cancer development is not clear. Breast cancer is associated with high local estrogen concentrations. This steroid hormone can be produced locally from estrone by 17B-HSD 1 which has been shown to be inhibited by genistein and coumestrol. Other sources of estradiol would be production from testosterone which is built by 17B-HSD 5 and converted by aromatase. To some extent 17B-HSD 5 converts estrone to estradiol. Consequently an inhibition of this enzyme might effect the local production of active estrogens and thus influence breast cancer development.
One interesting effect is seen in the inhibitory capacity of 18B-glycyrrhetinic acid. This substance found in licorice does not influence the oxidative pathway but inhibits reduction of androstenedione to testosterone. Previously it has been observed that the serum testosterone level is significantly reduced in men consuming about 7g of a commercial preparation of licorice (containing 0.5g of 18B-glycyrrhetinic acid) a day. It has been demonstrated that licorice consumption inhibits 11B-hHSD, and 17B-hHSD and 17,20-lyase activity. Reduced 17B-HSD activity might be due to inhibiton of 17B-hHSD type 3 or 5. Decreased testosterone levels result in reduced libido or other sexual dysfunction but might have beneficial effects in cases of abnormal prostate growth.
We conclude that 17B-HSD 5 is a potential target for the inhibitory effect of a variety of phytoestrogens. This inhibition might contribute significantly to the cancer preventive action of a soy-based diet.

Also check out the Tables!

Mostly the same as the previous, but it has some other figures as well.
The most common prostatic diseases, which are benign hyperplasia (BHP) and prostate cancer, are treated by androgen ablation. Testosterone deprivation leads to the loss of secretory function and reduction in glandular size caused by the widespread apoptosis in this organ. In histoculture studies, genistein decreases growth of both BHP and prostate cancer tissues. Increased apoptosis has been reported in implanted prostate cancer in rats and mice after dietary intake of soy food containing high amounts of flavonoids. Additionally, epidemiological studies support cancer preventive action of phytoestrogens. In Japan, where a soy-based phytoestrogen-rich diet is consumed, the incidence of latent and small or noninfiltrative prostatic carcinoma is the same as in Western countries, but the resulting mortality from this is much lower.
Influencing the local androgen concentration by modulating the 17B-HSD activity of 17B-HSD 5 in androgen synthesis, normal or abnormal growth of the androgensensitive prostatic gland might be affected.
However, soybeans have been shown to inhibit mammary tumors in models of breast cancer, and genistein may block the growth of epithelial cells by interfering with signal transduction events stimulated by estradiol. Genistein, the less potent isoflavones biochanin A and daidzein inhibit growth of human breast cancer cells in vitro independent of the presence of the estrogen receptor. Anyway, it is not clear whether effects on reduced growth of breast cancer cells are due to 17B-HSD 5 inhibition.

I may not have to worry about gynecomastia if I have a depletion of estrogen, but this still looked very interesting.
A few cases of gynecomastia caused by the rare disorders aromatase excess syndrome and Peutz–Jeghers syndrome have responded to treatment with AIs such as anastrozole. Androgens/anabolic steroids may be effective for gynecomastia. Testosterone itself may not be suitable to treat gynecomastia as it can be aromatized into estradiol, but nonaromatizable androgens like topical androstanolone (dihydrotestosterone) can be useful.
Certain health problems in men such as liver disease, kidney failure, or low testosterone can cause breast growth in men. Drugs and liver disease are the most common cause in adults. Other medications known to cause gynecomastia include methadone; aldosterone antagonists (spironolactone and eplerenone); HIV medication; cancer chemotherapy; hormone treatment for prostate cancer; heartburn and ulcer medications; calcium channel blockers; antifungal medications such as ketoconazole; antibiotics such as metronidazole; tricyclic antidepressants such as amitriptyline; and herbals such as lavender, tea tree oil, and dong quai.
About 10–25% of cases are estimated to result from the use of medications, known as nonphysiologic gynecomastia. Medications known to cause gynecomastia include cimetidine, ketoconazole, gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, 5a-reductase inhibitors such as finasteride and dutasteride, certain estrogens used for prostate cancer, and antiandrogens such as bicalutamide, flutamide, and spironolactone.
Medications that are probably associated with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine; risperidone, olanzapine, anabolic steroids, alcohol, opioids, efavirenz, alkylating agents, and omeprazole. Certain components of personal skin care products such as lavender essential oil or tea tree oil and certain dietary supplements such as dong quai and Tribulus terrestris have been associated with gynecomastia.

The overexpression of aromatase leads to high estrogen levels, so aromatase underexpression should be considered as well.

In normal individuals, a painful/stressful stimulus up-regulates Substance P in the nociceptive relay neurons and serotonin levels drop, consistent with a loss of feeling of well-being. Substance P has been found to stimulate aromatase, which would catalyze the conversion of testosterone to estradiol within the CNS, with subsequent upregulation of opiates and consequent dampening of pain. In fibromyalgia patients, deficient levels of testosterone are predicted to result in a "frustrated" cycle (due to lack of substrate) in which conversion of testosterone to estradiol is inadequate for induction of opiate-mediated dampening of nociceptive signals, resulting in abnormal chronic, diffuse, widespread pain. Estradiol, refers to 17-beta estradiol.

However, in the presence of acerola cherry extract, both soy and alfalfa extracts potently inhibited the formation of low-density lipoprotein (LDL). These findings show that acerola cherry extract can enhance the antioxidant activity of soy and alfalfa extracts in a variety of LDL oxidation systems. The protective effect of these extracts is attributed to the presence of flavonoids in soy and alfalfa extracts and ascorbic acid in acerola cherry extract, which may act synergistically as antioxidants. It is postulated that this synergistic interaction among phytoestrogens, flavonoids, and ascorbic acid is due to the "peroxidolitic" action of ascorbic acid, which facilitates the copper-dependent decomposition of LDL peroxides to nonradical products; this synergy is complemented by a mechanism in which phytoestrogens stabilize the LDL structure and suppress the propagation of radical chain reactions.
The combination of these extracts markedly lowers the concentrations of phytoestrogens required to achieve significant antioxidant activity toward LDL.
Title: Re: FAAH Inhibitors
Post by: berlin1984 on May 15, 2021, 02:10:54 PM
You are writing a lot of text and even the bold-ing does not help to process it.

Maybe it would help if you start the post with a tl;dr summary at the top? like with bullet points or so?
(I know you might be writing a lot just for yourself to process the thought flow)

@Quantum: Is there a way to have the forum theme to not have those endless long lines? But more something which has a fixed length of paragraph, like a book?

That said, I actually have alfalfa extract here because when I was following the testosterone deficit theory I wanted to have it boost my testosterone..
If you search the forum, it comes up a bit. <- for example this guy with the questionable nickname takes it (together with Ashwagandha which I love)
Title: Re: FAAH Inhibitors
Post by: berlin1984 on May 18, 2021, 07:07:15 AM
Nice summary now in:
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 18, 2021, 02:35:57 PM
You are writing a lot of text and even the bold-ing does not help to process it.

Maybe it would help if you start the post with a tl;dr summary at the top? like with bullet points or so?
(I know you might be writing a lot just for yourself to process the thought flow)

@Quantum: Is there a way to have the forum theme to not have those endless long lines? But more something which has a fixed length of paragraph, like a book?

That said, I actually have alfalfa extract here because when I was following the testosterone deficit theory I wanted to have it boost my testosterone..
If you search the forum, it comes up a bit. <- for example this guy with the questionable nickname takes it (together with Ashwagandha which I love)

I am sorry if it is inconvenient, I will try to further reduce the text. I also don't think I will add much more on the theoretical background, so you don't have to worry about the clogging.
You guessed it right as it helps me to have an overview, but I also wanted to give some new ideas for those who would be interested.
I am currently writing a post about estrogen as it turns out to down-regulate FAAH expression, which means that I may have come to a full circle.
Of course this doesn't explain the exact disease pathology, but it is major evidence that FAAH inhibitors are really the best treatment for my ail.
I didn't know that alfalfa can increase testosterone levels, but you could be right. This is a good study, however the researchers neglected to mention that alfalfa contains other phytoestrogens as well like the potent coumestrol.
As indicated earlier a low level of testosterone and Tribulus terrestris can both contribute to gynecomastia development, which doesn't take well with a purely testosterone hypothesis.
I think we really need to consider the fibromyalgia hypothesis as it indicates a close interrelationship between both testosterone and estrogen and a depletion of both could be an actuality.
Maybe there is a biofeedback in aromatase activity and an increased estrogen level (due to supplementation) would normally result in a reduced conversion with a concomitant increase in testosterone as well. Of course the involvement of hydroxysteroid dehydrogenase activity can't be excluded in this.
By the way have you ever tried CBD oil?
Title: Re: FAAH Inhibitors
Post by: berlin1984 on May 20, 2021, 02:33:56 AM
More saffron testimonial:
Yes, I tried saffron, it removes 90% of my brain fog, the only problem that remains is visual blur and photosensitivity.
Title: Re: FAAH Inhibitors
Post by: Progecitor on May 31, 2021, 11:08:02 AM
Although it remains unclear how sex may affect the initiation and maintenance of cannabis use in humans, animal studies strongly suggest that endogenous sex hormones modulate cannabinoid sensitivity. In addition, synthetic anabolic-androgenic steroids alter substance use and further support the importance of sex steroids in controlling drug sensitivity. The recent discovery that pregnenolone, the precursor of all steroid hormones, controls cannabinoid receptor activation corroborates the link between steroid hormones and the endocannabinoid system.
Sex hormones are synthesized by conversion of cholesterol into pregnenolone, which is the precursor of all steroid hormones. Interestingly, pregnenolone protects the brain from cannabinoid type-1 receptor (CB1R) overactivation, by acting as a potent endogenous allosteric inhibitor of CB1Rs, and prevents cannabinoid-induced psychosis in mice. Sex hormones can be divided into three main subtypes with distinct molecular functions and sexually dimorphic expression and distribution: androgens (e.g., testosterone, dehydroepiandrosterone, androstenedione), estrogens (e.g., 17-alpha and 17-beta estradiol, estrone, estriol) and progestogens (e.g., progesterone, allopregnanolone, pregnenolone). Sex hormones are produced by the gonads in response to the stimulating activity of the pituitary gonadotropins whose release is, in turn, under the control of the hypothalamic gonadotropin releasing hormone (GnRH). At the central level, several neurotransmitters are able to modify the release of GnRH, including norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and glutamate. Cannabinoids were found to significantly modulate the activity of the hypothalamic-pituitary-gonadal (HPG) and -adrenal (HPA) axes and their interactions. Interestingly, sex hormones influence the action of cannabinoids on these axes suggesting bidirectional interactions between sex hormones and the endocannabinoid system.
González et al. found that males have higher levels of CB1R-mRNA transcripts than females in the anterior pituitary gland but that, in females, CB1R-mRNA transcripts fluctuate during the different phases of the ovarian cycle with the highest expression on the second day of diestrus and the lowest expression on estrus. Based on these findings it was suggested that higher levels of estrogen in the anterior pituitary gland could serve to inhibit CB1R expression, reducing the inhibitory endocannabinoid tone within the HPG axis around the time of ovulation. More recently, Castelli et al. found that CB1R density was significantly lower in the prefrontal cortex (PFC) and amygdala of cycling females compared to males and ovariectomized (OVX) females, and that administration of estradiol to OVX markedly reduced the density of CB1Rs to the levels observed in cycling females. In addition, OVX females displayed higher CB1R function in the cingulate cortex compared to intact and OVX + estradiol females. Interestingly, sex and estradiol also affected motor activity, social behavior and sensorimotor gating, which are behaviors sensitive to the effects of different classes of drugs of abuse, in line with the idea that females can represent a more vulnerable phenotype (at neurochemical and behavioral level) than male rats in developing addiction-like behaviors. In addition, estradiol time-dependently modulates CB1R binding in brain structures that mediate nociception and locomotor activity.
The following findings are consistent among studies: (i) higher density of CB1Rs in male hypothalamus and limbic areas coupled, in general, with lower levels of endocannabinoids; (ii) there are significant differences along the hormonal cycle of females, with major changes occurring in the expression of CB1Rs in pituitary gland, hypothalamus and midbrain limbic structures when passing from diestrus to proestrus and behavioral estrus.
Sex steroids, like estrogens, can also regulate the activity of the endocannabinoid metabolizing enzymes. Fatty Acid Amide Hydrolase (FAAH) is the main enzyme involved in the degradation of AEA. The promoter region of the FAAH gene contains an estrogen binding response element, and translocation of the estrogen receptor to the nucleus results in repression of FAAH transcription in vitro and in vivo. Ovariectomy prevents the estrogen-induced down-regulation of FAAH expression, and both progesterone and estrogen reduce basal levels of FAAH.
In humans, plasma AEA levels fluctuate across the menstrual cycle, with a peak at ovulation and the lowest plasma AEA levels observed during the late luteal phase. In addition, significant positive correlations exist between plasma levels of AEA and plasma levels of estradiol, luteinizing (LH) and follicle-stimulating hormone (FSH) levels.
While some of the sexual dimorphisms in the brain endocannabinoid system might be permanent, cannabinoid sensitivity is not fixed and can be acutely modulated by hormone-dependent fluctuations of CB1R density, levels of endocannabinoids and of endocannabinoid metabolizing enzymes.
Sexual maturation takes place under hormonal control during puberty and adolescence. Exposure to cannabinoids during critical developmental periods alters several functions in adult animals including working and spatial memory, sensorimotor gating, anxiety and anxiolytic-like responses, anhedonia, depressive-like states and sexual behavior.

Estradiol and progesterone rapidly induce changes in dopaminergic signaling within the dorsal striatum and nucleus accumbens of female rats, effects that are important for the regulation of normal physiological states and relevant reproductive behaviors. While the enhancing effect of ovarian hormones on drug craving has been traditionally attributed to estrogens (even in view of their ability to elicit direct dopamine release in the brain), it was suggested that progesterone, rather than estradiol, is responsible for the reducing effect on drug-seeking behavior.
The leading hypothesis that sex steroids and (endo)cannabinoid actions can converge on the dopaminergic mesolimbic system to regulate important motivational aspects in a sexually dimorphic manner deserves further confirmation.
It was shown that testosterone significantly reduces THC-induced locomotor suppression or catalepsy in gonadectomized males and that chronic exposure to nandrolone, a derivative of testosterone also known as 19-nortestosterone, blocked THC-induced conditioned place preference in rats. Further, we recently reported that chronic treatment of rats with nandrolone does not alter CB1R levels or function in several reward-related brain areas. However, when chronic nandrolone treatment is followed by cannabinoid self-administration, we observed a strong decrease in CB1R function in the hippocampus and a significant increase in cannabinoid intake. Given the profound effects that anabolic-androgenic steroids (AAS) have on various aspects of the molecular machinery of the brain reward system, it might come as no surprise that AAS also interfere with the rewarding properties of drugs of abuse, including cannabinoids.

Using MA-10 cells treated withe G protein-coupled estrogen receptor (GPER) and PPAR antagonists (alone and in combination), we demonstrated GPER-PPAR–mediated control of estradiol secretion via GPER-PPARA and cyclic guanosine monophosphate (cGMP) concentration via GPER-PPARG. It is assumed that GPER and PPAR can crosstalk, and this can be altered in Leydig cell tumor (LCT; leydigioma), resulting in a perturbed lipid balance and steroidogenesis. In LCTs, the phosphatidylinositol-3-kinase (PI3K)-Akt-mTOR pathway was disturbed. Thus, PI3K-Akt-mTOR with cGMP can play a role in LCT outcome and biology including lipid metabolism.
Alternatively, an excess of various hormones (e.g., estrogen, prolactin) produce elevated LH levels that excessively stimulate steroidogenic Leydig cell function. Overproliferation of Leydig cells may result in the synthesis of non-functional steroid hormones.
Mitogenicity associated with estrogen receptor–mediated cellular events is believed to be the mechanism by which estrogens contribute to tumorigenesis.
A central factor in LCT growth and progression is represented by an inadequate intratesticular balance in the androgen/estrogen ratio with advantage of the latter hormone.
Herein, we revealed an increase in GPER expression in LCTs. Also in our in vitro experiments in mouse tumor Leydig cells, GPER expression was increased. Taken together, it is likely that various estrogen pathways may be deregulated in LCTs, which reflects tumor heterogeneity and may contribute to its development.
Herein, we showed GPER, alone and together with PPARA, affected estradiol secretion by tumor Leydig cells. Such result indicates on a leading role of GPER in regulation of sex hormone production and secretion and concomitantly suggests possible GPER and PPARA alterations in LCTs. Similarly, our prior study also showed progesterone secretion modulation in GPER and PPAR antagonist-treated tumor mouse Leydig cells. According to findings by Chimento et al. GPER is a good target for reduction of tumor Leydig cell proliferation that is hormonally controlled.
We showed, for the first time, a PPAR expression pattern in normal human Leydig cells and its prominent downregulation in LCT. An opposite correlation was found in dog testis, and PPAR
expression was always markedly higher in tumor tissue. Notably, confusing results were seen concerning the involvement of PPAR in tumor biology. PPAR was revealed to both promote and inhibit cancer via effects on cell differentiation, growth, metastasis, and lipid metabolism.
Therefore, these results demonstrated that GPER- and PPARA-mediated pathways are involved in the maintenance of mTOR activity, whereas PPARG signaling has an opposite effect, reducing mTOR activity.

CB1R signalling, as well as fatty acid amide hydrolase (FAAH) inhibition, are associated with decreased pro-inflammatory cytokines. Moreover, activation of CBRs is required for neurogenesis, which is also upregulated by FAAH inhibitors.
Title: Re: FAAH Inhibitors
Post by: Progecitor on June 03, 2021, 03:27:10 PM
A role for AKR1C3 still can't be ruled out!
AKR1C3 is therefore implicated in regulating ligand access to the androgen receptor, estrogen receptor, and PPARG in hormone target tissues. Recent reports on close relationships between ARK1C3 and various cancers including breast and prostate cancers implicate the involvement of AKR1C3 in cancer development or progression.
Tissue distribution of human AKR1C3 and its rat homolog in adult genitourinary systems including kidney, bladder, prostate, and testis was studied by IHC.
Natural substrates for these enzymes include steroids, prostaglandins (PGs), and lipid aldehydes.
AKR1C3 catalyzes androgen, estrogen, PG, and xenobiotics metabolism. The relatively high 17B-HSD activity of this enzyme reduces d4-androstene-3,17-dione (a weak androgen) to yield testosterone (a potent androgen) and reduces estrone (a weak estrogen) to yield 17B-estradiol (a potent estrogen). Using its 3a-HSD activity, AKR1C3 reduces 5a-dihydrotesterone (5a-DHT, a potent androgen) to 5?-androstane-3a,17B-diol (3a-diol, a weak androgen). AKR1C3 also possesses PG 11-ketoreductase activity to reduce PGD2 to 9a,11B-PGF2a. As a result, AKR1C3 may deprive PGJ2, a ligand for PPARG and lead to suppressed cell differentiation. AKR1C3 is therefore capable of governing ligand access to various nuclear receptors.
We have suggested that AKR1C3 is an enzyme that is poised to govern steroid hormone action at the prereceptor level by governing ligand access to the appropriate nuclear receptor, including the androgen receptor (AR), the estrogen receptor (ER), and the PPARG, in hormone target tissues.
AKR1C3 may also be playing a role in gland maintenance within the prostate and in sexual response with stromal contraction during ejaculation.

AKR1C3, and its rat homolog, may as also be serving to facilitate the turn over of old epithelial cells with new ones in a fashion similar to that seen within the intestines.
One significant note about the expression of AKR1C3 in the various human tissues is that the endothelial lining of non-specialized blood vessels showed strong positive immunoreactivity. The exact role that AKR1C3 is playing in blood vessels is unknown. With the suggested involvement of AKR1C3 in PG metabolism, the role of AKR1C3 in endothelial cells may be closely related to and/or regulated by the PG metabolism.

This may put Indomethacin in a whole new light.
Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2.
Title: Re: FAAH Inhibitors
Post by: berlin1984 on June 04, 2021, 03:01:51 PM
Hm. I should not have bought an alcohol-free extract of lungwort (
Extraxt with glycerin, water, lungwort.
I should have bought (tea) leaves like you.

I can't say I feel anything from that extract.
Tried it a few times now in the last weeks.
Maybe I think it gives some feeling that I need to take a deep breath, but this could just be imagination.

Maybe you can elaborate a bit more (except for the chest pain effect it had when taking it first, might be coincidence?).
How does it differ if you take it related to orgasm or not, related to POIS or not?

You just take tea, right? So it's also not the the ethanol extract that you mentioned.

Regarding your question about CBD: Tried it a few times, I think it was nice. But my bottle ran out and I didn't buy a new one because I read it has bad effects on sperm.
If we manage to have a second child, I can finally experiment with more stuff that has bad effect on fertilitity, like Bacopa Monnieri (  :P
Title: Re: FAAH Inhibitors
Post by: Disaster on June 07, 2021, 12:56:27 AM
This is a crazy amount of information and I tried to read a lot of it but honestly every time you go into something it seems like you are grasping at straws. Remember something can seem like one thing from symptoms but in reality be something else entirely different. I can?t even imagine how many times you thought it was one thing and then moved onto something else. You may find lots of things that help you like the CBD oil but that might not lead to the actual explanation of shy it is helping you. That is true with many herbs, supplements and medication. Idk that you have to label, it would just be more helpful for everyone if you just listed your symptoms and listed what you are experimenting with and how it helped you. Which you did but on top of that a mountain of opinions and research makes it hard to get through..
Title: Re: FAAH Inhibitors
Post by: Progecitor on June 08, 2021, 03:48:58 PM
Hm. I should not have bought an alcohol-free extract of lungwort (
Extraxt with glycerin, water, lungwort.
I should have bought (tea) leaves like you.

I can't say I feel anything from that extract.
Tried it a few times now in the last weeks.
Maybe I think it gives some feeling that I need to take a deep breath, but this could just be imagination.

Maybe you can elaborate a bit more (except for the chest pain effect it had when taking it first, might be coincidence?).
How does it differ if you take it related to orgasm or not, related to POIS or not?

You just take tea, right? So it's also not the the ethanol extract that you mentioned.

Regarding your question about CBD: Tried it a few times, I think it was nice. But my bottle ran out and I didn't buy a new one because I read it has bad effects on sperm.
If we manage to have a second child, I can finally experiment with more stuff that has bad effect on fertilitity, like Bacopa Monnieri (  :P

I am sorry to hear that lungwort hasn't worked for you so far. I also want to test the extract form you tried, but I can't make a comparison as of yet. Also consider that I usually use about 2 spoonful of leaves with more than 1 liter of hot water. Please note that currently I am not trying to treat myself, but rather to sort out which supplements are beneficial or detrimental, so I move on to something new even when I find something good. Later I will try to combine the beneficial ones, but I bought a lot of other supplements that I want to try out beforehand. I only used lungwort tea a few times, but it was surely beneficial when I had depressive POIS. The benefit of lungwort is that it has quite a rapid effect (1-2 hours), however its effectiveness also vanes quickly so it is a good urgent remedy, but not something to really hold off POIS.

Some other experiences I had:
- Chia seeds: I used about one spoon (2 bigger teaspoon) of chia seed in the morning and one in the evening. I put it in a cup of water and waited 10-15 minutes before consuming it. An effect can be seen in about 6-9 hours. Chia seeds don't have a great impact on depression or POIS symptoms, but they can definitely reduce the burning pain by next day. Stool quality is also much better. By taking chia in the evening and drinking saffron tea in the morning I may finally be able to get rid of coffee entirely.
Chia seeds are considered PPARA agonists, so this may be a reason why it could be beneficial.
- Magnesium [795 mg per pill]: The pure form is also beneficial on stool quality, although I don't think it did anything to the burning pain. I may have misjudged magnesium based on my past experiences, but I still need to test it more. In the past I used combined magnesium and vitamin B6 pills and I think vitamin B6 makes me somehow ill, although probably not in a POIS-like manner.
- Physalis peruviana (inca berry): As far as I could judge it had a good quality. I tested it against an O by consuming 20 pieces 3 hours before O than 20 pieces right after O then 20 pieces again a few hours later but it doesn't look like if it has any great effect. It did nothing to depression and I still had symptoms, although I think it somewhat reduced the bloodshot eyes symptom. I couldn't figure out how it affected the burning pain, so I will need to test it some more. With so little effect it is certainly not a cost-effective treatment for me. Maybe I could try making a tea from the berries and see if it is any better that way.
- Safflower spice (Carthamus tinctorius) which is also referred to as bastard saffron [1 liter tea made with two spoonful of dried safflower stigmas]: I though it could be interesting to test and compare it to saffron. I can conclude that bastard saffron certainly doesn't have any anti-depressive effects like saffron. At least it seems to have weakly reduced the burning pain, so it is not something bad at least. From its seed they also produce oil which I may test later.
- Oregano: I made a tea from the spice I had at home and consumed 7 deciliter of the stuff. It has an interesting and potent taste. I am quite certain that oregano tea induces bloodshot eyes. I slept very poorly that night, but I don't know if it was due to oregano or not. In the next morning the stool quality was better, but the burning pain was present, however I couldn't judge if oregano actually induced it or not, so I need to test it more.
- Papaya pills [papaya leaves and fruit powder – 500 mg per pill]: Papaya pills certainly have a positive effect. I think it has a weak effect on depression and can reduce other symptoms to a weak-moderate level. The problem is that I need to take several pills for a noticeable effect and this doesn't make papaya pills cost-effective as they are not exactly cheap.
- Lavender: I just rechecked what I wrote about lavender tea and realized that I neglected to mention that it has a really good effect on depression. I think this becomes really apparent after about 5 hours and lasts quite long. I think it could be combined well with saffron and lungwort which have a more rapid, but shorter lasting effect. 

By chance I came across something that seemed interesting. In order to restore hormonal balance google recommends lavender, raspberry leaves, tea tree oil and oat straw. Interestingly lavender and tea tree oil are also indicated as disruptors of hormonal balance. Lavender and tea tree oil have an estogenic and an anti-androgenic effect.

As lavender was beneficial I thought I would give a try to the rest as well.
Raspberry leaves (Rubi idaei folium): The tea made from raspberry leaves turned out to have a really positive effect.
It only has a weak effect on depression, but it can definitely ameliorate POIS symptoms. I tested it against an O by drinking the tea before and after ejaculation and it couldn't prevent the occurrence of symptoms, but by next day I can still see a clear difference. Raspberry leaves contain some of the previously mentioned flavanoids, however what seems to be more interesting is that it also contains some phytosterols (B-sitosterol, stigmasterol) as well.
Phytosterols are actually considered as xenoestrogens. Check the bottom of the page for an extensive list of androgen and estrogen receptor modulators.

Tea tree oil [4 drops on a teaspoon of sugar]: I only tried tea tree oil once, but I think it also has a positive effect.
Oat straw is Avena sativa which is actually a component of the combined Echinacea and Avena sativa pills I had some success with. The pills only contained 50 mg Avena sativa, however it is also sold as a standalone supplement with 250 mg of content, so I feel I have to test that as well.

I read most of your post, but I don't remember if you ever had your testosterone or estrogen levels checked. Could it be that vaginal estrogen is the reason why sex with a woman results in less POIS? Does the use of a condom matter in this regard?

I tried testing fenugreek by taking it two hours before an O, however it changed nothing and I was forced to take other effective medication. I am going to test it further to see if it does anything by a longer term use.

Some other background information:
Check out Table 3 for scientifically proven testosterone enhancers!
Table 3. Published evidence showing an increase, decrease or no change in testosterone (T) with supplementation

Chia intake increased HDL cholesterol (HDL-c) and reduced LDL cholesterol (LDL-c) levels. PPARA mRNA expression was elevated, and levels of NF-kB mRNA expression were reduced in the STC group. mRNA expression and protein levels of TNF-a were lower in rats fed the standard diet. Protein levels of IL-1B were reduced in rats fed the standard diet, and the high fat diet with chia.
Chia intake improved antioxidant activity by increasing SOD expression, PPARA expression, catalase activity, and HDL-c levels. In addition, chia consumption decreased the concentrations of the inflammatory markers IL-1B and LDL-c.!divAbstract

Raspberry leaves (Rubi idaei folium) are a source of flavonoids, gallic tannins, phenolcarboxylic acids, sterols, vitamin C and oligoelements (selenium, vanadium). The leaves are not mentioned by the scientific literature for their possible use in metabolic diseases (diabetes, dyslipidaemia, hyperuricaemia), but among their compounds, polyphenols, sterols and vitamin C might be responsible for these properties.
Using HPLC gallic, chlorogenic, caffeic, p-coumaric and ferulic acids, tannin, rutin, quercetin and catechin were identified in young leaves; rutin (0.0540 g%) and p-coumaric acid (0.03174 g%) were also quantified.
According to the scientific literature, raspberry leaves have antioxidant properties, being a source of: 0.46–5% flavonoids (rutin = quercetin-3-O-rutinoside, hyperoside = quercetin-3-O-galactoside, tiliroside = kaempferol-3-O-B-D(6’’E-p-coumaroyl) glucopyranoside and other heterosides of myricetin, kaempferol, quercetin, isorhamnetin); 2.06–6.89% gallic tannins as monomers and polymers (sanguiin H6, lambertianin C), phenolcarboxylic acids = AFC (gallic, chlorogenic, gentisic, ellagic, caffeic, ferulic, lithospermic, p-coumaric acids); sterols (B-sitosterol, stigmasterol); vitamin C and oligoelements (selenium = 19–381 ug/kg, vanadium = 138–1958 ug/kg).
Myricetin acts as a potent inhibitor of xanthinoxidase’s activity and lithospermic acid raises glomerular filtration rate.

Carica papaya is a tropical plant species discovered to contain high amounts of natural antioxidants that can usually be found in their leaves, fruits and seeds. It contains various chemical compounds demonstrate significant antioxidant properties including caffeic acid, myricetin, rutin, quercetin, a-tocopherol, papain, benzyl isothiocyanate (BiTC), and kaempferol. Therefore, it can counteract pro-oxidants via a number of signaling pathways that either promote the expression of antioxidant enzymes or reduce ROS production.
Papain is the most widely exploited proteolytic enzyme from the Carica papaya L. and it has been used to help with meat tenderization and digestion. It is worth to note that papain exhibited great potential as a medication, as it is suggested to exhibit drug-like properties for atherosclerosis and associated conditions, which involve monocyte-platelet aggregate (MPA)-regulated inflammation.
ROS are produced to eliminate invaders whereby activates Nuclear factor kappa-B (NF-kB). NF-kB is a transcription factor and plays a role in inducing inducible nitric oxide synthase (iNOS) activity and, thus, nitric oxide (NO) production. Excessive ROS upregulated prostaglandin E2 (PGE2) synthesis and, hence, cyclooxygenase-2 (COX-2) expression, which eventually leads to oxidative stress that causes tissue damage and worsens inflammation.
Another study further suggested that oxidative stress and inflammation are interrelated as oxidative stress resulting from high ROS can precipitate the formation of inflammation by increasing the gene expression coding for inflammatory proteins, including NF-kB, peroxisome proliferator activator receptor gamma (PPARG), and activator protein 1 (AP-1). Consequently, inflammatory chemokines and cytokines are produced to induce inflammation.
Somanah and co-workers revealed that papaya extracts at a dose of 2 mg/mL showed protective effects through attenuated ROS production and pro-inflammatory cytokines secretion of interleukin-6 (IL-6) and TNF-a as well as upregulating antioxidant enzymes activities. Another in vivo study showed that papaya juice demonstrated anti-obesity properties by reducing obesity markers, inflammation and oxidative stress in high-fat diet rats by upregulating SOD levels, attenuated serum malondialdehyde (MDA), PPARG, lipid peroxidation, and ROS production at a treatment dose of 1 mL per 100 g of body weight.
In addition, a range of phytochemicals with great strength of anti-inflammatory effect, such as benzyl isothiocyanate (BiTC), B-carotene, lycopene, and vitamin C could be found in various parts of papaya fruits, in either pulp or seeds. These phytochemicals were proven to inhibit pro-inflammatory cytokines including TNF-a, IL-6 and monocyte chemoattractant protein-1 (MCP-1).
The further study showed that addition of selenium to the papaya fruit extract synergistically upregulated TGF-B and VEGFA resulting in a significant acceleration in the wound healing process.
Title: Re: FAAH Inhibitors
Post by: Progecitor on June 09, 2021, 03:31:28 PM
This is a crazy amount of information and I tried to read a lot of it but honestly every time you go into something it seems like you are grasping at straws. Remember something can seem like one thing from symptoms but in reality be something else entirely different. I can?t even imagine how many times you thought it was one thing and then moved onto something else. You may find lots of things that help you like the CBD oil but that might not lead to the actual explanation of shy it is helping you. That is true with many herbs, supplements and medication. Idk that you have to label, it would just be more helpful for everyone if you just listed your symptoms and listed what you are experimenting with and how it helped you. Which you did but on top of that a mountain of opinions and research makes it hard to get through..

It is true that I have ventured many avenues, but I feel I am currently on the right track in figuring this out. I think many of the factors I highlighted are intricately involved in my POIS type, but what I couldn't figure out is which is the most important component, where all the trouble starts. It seems undeniable that the endocannabinoid system (ECS) has a major role in my case. However the ECS is very complex with far reaching effects and thus difficult to disentangle. This may also indicate why POIS causes so many symptoms. The ECS has a crucial role in the acrosomal reaction, thus establishing a connection with sexual activity. As of now it seems very likely that FAAH inhibitors and PPARA agonists are beneficial for me. TRPV1 activation is almost certain (capsaicin-like) and CB receptor antagonists (e.g. Rimonabant) were shown to be able to induce flu-like symptoms. FAAH inhibition increases the levels of N-acylethanolamines among which anandamide is the most important as it is an agonist of CB receptors and can activate or desensitize TRPV1 receptors. TRPV1 activation upregulates NOS and may lead to oxidative stress. NO inhibitor supplements seem to be beneficial in my case, although PPARG agonists should do the same. PPARG agonists are highly controversial, but the involvement of PPARG is still very relevant. Furthermore PPARs are semi-permanently reprogrammable (e.g. by environmental chemicals, microbiome, etc.) and were shown to play a role in many neurodegenerative diseases and withdrawal. PPARA agonists have an estrogenic effect. As of now it may be possible that both androgenic and estrogenic supplements could be beneficial for me. There is nothing to indicate that I would have a low testosterone or a high estrogen level. Even if estrogen turned out to be normal after a measurement it could still mean that a high estrogen level is beneficial only because it contributes to FAAH inhibition. Although I had success with several phytoestrogens I also had trouble with some (the case of Kudzu), so I can't claim that they uniformely work for me. The list of xenoestrogens is really impressive if we consider that it mentions quercetin, kaempferol, apigenin, myricetin, naringenin, biochanin A, ECG, EGCG, resveratrol, lavender oil, glabrene, glabridin that were previously discussed. The agonists of GPER should be considered as well (e.g. niacin and nicotinamide).
Kudzu contains daidzin, daidzein, genistein and puerarin which are also phytoestrogens.  Daidzein and genistein are also FAAH inhibitors, so it is hard to see why Kudzu doesn't work. However daidzein and genistein doesn't inhibit some AKR1Cs.
AKR1C3 inhibitors also look to be beneficial. AKR1C3 has a role in ejaculation. AKR1C3 establishes a connection with androgen receptors, estrogen receptors and PPARG. AKR1C3 converts many hormones in a complex manner.
TLR4 and Nrf2 are not likely to be involved too much in my case. However I still mentioned them as they could play a role in other POIS or CFS cases. They also seem to play a role in COVID-19 along with FAAH and PPARG, so they could be important factors to figure out how POIS, CFS and postcovid syndrome are related.
Testing some proven drugs may help uncover the origin as well. If Indomethacin (AKR1C3 and COX inhibitor) proved to work it could clearly indicate the involvement of AKR1C3 as COX inhibitors like Aspirin didn't really affect my POIS. Testing Fenofibrate (PPARA agonist) and Pioglitazone (PPARG agonist) could be critical as no POISer seem to have tested them so far. Due to a lethal clinical trial there are no FAAH inhibitors on the market, so it can't be tested easily. I also couldn't find any lab that would measure this parameter. Androgen receptor antagonists (e.g. Dutasteride) and estrogen receptor antagonists (e.g. Tamoxifen (also AKR1C3 inhibitor)) could be tried as some POISer had success with them. As the ECS, opioid and serotonergic system is intricately connected it wouldn't hurt (well it could) to test opioid agonists (e.g. Tianeptine), opioid antagonists (e.g. Naltrexone), serotonergic agents (SSRIs, tryptophan, etc.) and different serotonin receptor inhibitors (e.g. Ondansetron (5-HT3 antagonist)) as well. Testing Rimonabant and CBD oil would be interesting as well.
Title: Re: FAAH Inhibitors
Post by: Progecitor on June 15, 2021, 02:02:36 PM
Testosterone suppresses PPARG activity, while estrogen behaves oppositely if applied in small (up-regulates PPARG) or high doses (down-regulates PPARG). PPARG shares co-activators with both ER and AR and they compete for co-activator binding.

Hormonal imbalances, either estrogenic or androgenic, have been reported to affect PPARG expression. A negative crosstalk between estrogens and PPARG expression levels is now well established in the literature, in both in vivo and in vitro conditions, mostly in human and mouse species, and particularly in cancer tissues and cell lines. Inhibition of PPARG by T or DHT was reported in a human kidney and prostate cancer cell lines, in mouse 3T3-L1 preadipocytes and in C3H 10T1/2 mouse pluripotent cells. Moreover, as a nuclear receptor, PPARG may be a potential target of xenobiotics, with either estrogenic or androgenic properties and therefore with potential endocrine disrupting effects.
Several studies in human, mouse and rat have reported that sex steroids such as E2, T, and DHT exert an effect on PPARG expression.
Sex-specific differences on PPARG gene expression may also exist. It is also well known that the pharmacological effect of pioglitazone, a PPARG agonist with hypoglycemic action in humans, differs between sexes, with women requiring a smaller treatment dose and experiencing higher side effects. These gender variations emphasize the role of sexual hormones on the modulation of this gene.
Despite the cited partial replication of in vivo vs. in vitro patterns, the exposure to EE2 revealed a paradoxical effect on PPARG gene expression. A non-monotonic response was obtained with the different doses of estrogen. The opposite results of lower and higher doses of EE2 on PPARG gene expression, revealed an apparent hormesis effect. Although this concept is not universally accepted, bidirectional dose responses to natural and xenoestrogens were previously observed in various contexts and organisms. Estrogens exert their effects through a diversity of pathways, which make them prone to hormetic responses. So, herein, the lowest dose (1 M of EE2) induced an increase on the PPARG mRNA levels and the opposite effect was obtained at the higher dose (50 M).
In the T experiment, a monotonic decrease of PPARG mRNA levels was observed after the higher doses (10 and 50 M).
In mouse 3T3-L1 cells matured into adipocytes, a significant increase in the PPARG protein levels was also found by western blot after 1 week of exposure to E2 at 10?9 M. Conversely, in white adipose tissue of ovariectomized mice the co-administration of troglitazone (PPARG agonist) and E2, both at 10 M, decreased the troglitazone induced upregulation of PPARG and target genes.
In fish, there are also conflicting results reporting up or downregulation of PPARG after estrogenic inputs. In zebrafish primary hepatocytes, PPARG mRNA was increased in response to 10 nM of EE2. In other study with the exact same model there was an increase in PPAR expression in parallel with a decrease in the percentage of PPARG immunolabeled positive cells, in response to 10 M of E2. Also in rainbow trout primary hepatocytes, the PPARG expression was significantly down-regulated at 30 nM of EE2.
Additionally, other less potent estrogenic compounds, namely phytoestrogens, nonylphenol, 4-tert-octylphenol, and bisphenolA have been also showing in vivo their interferences in PPARG mRNA expression in distinct fish species.
The diminishing of the PPARG mRNA we found, as a result of an androgenic stimulus, is in consensus with other in vivo and in vitro studies. In prenatal T-treated sheep, PPARG mRNAs in liver were significantly reduced in comparison with the control. Similar trends were obtained in vitro after exposure of a human kidney cell line to 10 nM of T, in a transcriptional transaction assay. In human prostate cancer cell lines exposed to 0.1–10 nM of DHT, a time and concentration dependent decrease was also observed.
In theory, the decreases in the PPARG mRNA levels as a consequence of steroid hormones exposure may be due to the activation of the nuclear receptors of the latter (i.e., ER or AR). Negative feedback relations between nuclear receptors may result from competition for co-activator binding, as it was already demonstrated. Accordingly, PPARG shares co-activators with both ER and AR. In addition, in the case of estrogens it has been suggested that eventually PPARG and ER may function as synergistic inducers.
However, as illustrated above, the interplay is very complex and conflictual results may arise from estrogenic and androgenic inputs, thus calling for further studies with more conditions and models.
Title: Re: FAAH Inhibitors
Post by: Progecitor on June 21, 2021, 12:50:17 PM
I may have neglected to emphasize that my POIS reacts to a lot of diet elements and in my opinion it is a rather convincing evidence of the involvement of PPARs. For many POISers the effective medications, besides their other effects, are known PPAR ligands and to me it seems almost undeniable that PPARs play a central role in our disease even if the same treatment may not work for everyone.

Natural ligands of the PPARs are fatty acids and numerous fatty acid derivatives. In addition, the PPARs can be activated by a variety of synthetic and natural compounds. The PPARs function by binding to specific DNA response elements as heterodimers with the retinoid X receptor. The fact that PPARs are activated by a large variety of metabolites has led to the notion that PPARs have an overall function as translators of nutritional signals into metabolic responses. Hence, they are crucially involved in the regulation of carbohydrate and lipid metabolism. PPARA is expressed in kidneys, liver, muscles, as well as in adipose tissues and activation results in up-regulation of genes involved in B-oxidation of fatty acids. Activation of the PPARD has been demonstrated to increase the expression of genes involved in glucose and lipid metabolism as well as regulation of energy expenditure. PPARG-1 is expressed in many tissues, notably in the gut, whereas expression of PPARG-2 is almost exclusively confined to adipose tissue, where it functions as a master regulator of adipocyte differentiation and plays a key role in the activation of genes controlling lipid metabolism and regulating insulin sensitivity. Different types of ligands can induce different sets of genes as the result of differential recruitment of co-factors. Hence, the transcriptional response following ligand-dependent activation of PPARG can be two-faced. Recruitment of some co-factors can lead to increased lipid storage and decreased energy expenditure, whereas recruitment of others increases insulin-stimulated glucose uptake, glucose metabolism and energy expenditure.
The thiazolidinediones (TZDs) are PPARG agonists prescribed as insulin sensitizing drugs for clinical management of T2D. The activation of PPARG by TZDs leads to a redistribution of fat from visceral to subcutaneous adipose tissue, increased trapping of fatty acids in adipose tissue, and a modified secretion of hormones from adipose tissue, all factors known to improve insulin sensitivity. However, administration of TZDs has been associated with severe side effects such as oedema, weight gain, heart enlargements and hepatotoxicity. The occurrence of undesirable side-effects has been linked to the use of TZDs behaving like full PPARG agonists. Partial PPARG agonists are ligands that upon binding to PPARG induce a conformation of the ligand-binding domain which differs from that induced by full agonists and thereby also recruits a different set of co-factors than these. It is generally recognized that the selective recruitment of co-factors in response to administration of a partial agonist do not induce the same magnitude of side-effects as observed for the full agonist TZDs. Therefore, the search for PPARG ligands with an improved mode of action is an important objective. Plants have a long history in the traditional treatment of diabetes and are a likely source of natural products with potential antidiabetic effects. It was therefore hypothesized that among common food and medicinal plants previously used as hypoglycaemic agents it would be possible to identify partial PPARG agonists, and hence promising plant candidates for the treatment of T2D.
Treatment with PPARA or PPARD agonists are associated with the development of cancer in rodents but also with beneficial effects such as improvement of the HDL/LDL cholesterol ratio hence, it is very important for the overall activity profiling of the extracts to include these assays.
French lilac, yellow meliot and milk vetch belong to the same plant family as fenugreek; the Fabaceae, and Species from this family have a long history of use in the traditional treatment of diabetes.

Table 2. lists some known modulators of POIS. It may be possible that PPARG agonists are so controversial, because of the aforementioned differential recruitment of co-factors. I plan to test as many of them as possible and this may shed some light on the matter.
A short list from Table 2:
Echinacea, origanum, marjoram, fenugreek, tartary buckwheat, goat's-rue or French lilac, sour cherry, Rhodiola roseal, sage, elderberry, summer savory, winter savory, thyme, nettle.

Title: Re: FAAH Inhibitors
Post by: Progecitor on June 23, 2021, 12:45:20 PM
Another great article with even more PPARG ligands related to gut health. Table 1 is especially informative as it also includes other inflammatory markers as well. It is of note that PPARG agonists and antagonists can both exert beneficial effects, however in my case some of them are actually detrimental.

Studies using polyphenol derivatives have also been demonstrated to inhibit a variety of biochemical pathways, including phospholipase A2, cyclooxygenase, lipoxygenase, and nuclear factor-kB (NF-kB) activation. These data suggest that the effect of polyphenols encompass more than just antioxidant activity. The anti-inflammatory effects of many polyphenols are mediated through activation of peroxisome proliferator activated receptors (PPARs), particularly PPARG. Even though the effect of PPARG ligands in treatment of diabetes and other diseases is positive, side effects such as weight gain, fluid retention, and increased risk of heart failure have prevented their long-term use.
Table 1 describes the anti-inflammatory properties of the following phytochemicals:
rhizome of Polygonum multiflorum (THSG), 2-Hydroxyethyl-5-chloro-4,5-didehydrojasmonate, abscisic acid (ABA) - a "classical" ubiquitious plant hormone, Alliin (S-allyl cysteine sulfoxide) - garlic, Amorfrutins (Amorpha fruticosa) and edible roots of Glycyrrhiza foetida (licorice), Andrographolide (Andrographis paniculata), Bergenin (also known as cuscutin) plants such as Bergenial crassifolia, Corylopsis spicata, Caesalpinia digyna, Mallotus japonicus, and Sacoglottis gabonensis, Cannabidiol (CBD), Conjugated linoleic acid (CLA), Curcumin is a polyphenol derived from Curcuma longa, Geniposide, an iridoid glycoside extracted from the fruit of Gardenia jasminoides Ellis, Geraniol is a terpene occurring in the essential oils of several aromatic plants like palmarosa, ninde, rose, and citronella oils, Glycyrrhizin (triterpenoid glycoside or saponin) is the primary sweet tasting constituent found in licorice root, Glycyrrhiza glabra L, B-glucans are a family of B-D-glucose polysaccharides found in the cell walls of cereals, bacteria and fungi. B-glucans from Shiitake mushrooms (Lentinus edodes), Magnolol Magnolia officinalis or in Magnolia grandiflora, Oroxyloside is a metabolite of oroxylin A from the root of Scutellaria baicalensisis, Oxylipins are a family of oxygenated products formed from polyunsaturated fatty acids by cyclooxygenases and lipoxygenases which are widely distributed in animals, plants, mosses, algae, bacteria and fungi, Punicic acid is a bioactive compound of pomegranate seed oil, Resveratrol is a natural polyphenol found in grapes, red wine, grape juice, and several species of berries, Tetramethylpyrazine (ligustrazine) is a compound isolated from Ligusticum wallichii, which has been extensively used for Chinese herbal medicine for centuries, Verbascoside is a member of a large family of phenylpropanoid glycosides that are widespread in the plant kingdom. Phenylethanoid verbascoside, isolated from Plantago lanceolata L., a-Eleostearic acid is isolated from tung and bitter gourd seed oils, B-Caryophyllene (BCP) is a natural bicyclic sesquiterpene present in significant amounts in natural products for example, clove oil, cinnamon leaves, and copaiba balsam, Portulaca oleracea L. (POL) is a traditional Chinese herb praised for its rich multi-minerals, proteins, a-amyrin, B-carotene, terpenoids, vitamins, and fatty acids, Zanthoxylum bungeanum Maxim. (Rutaceae) is a popular food additive and traditional Chinese herbal medicine commonly referred to as HuaJiao,

Imbalance of that milieu and gut dysbiosis in general has been associated with various health problems, including IBD. When dextran sodium sulfate-induced colitis mice are treated with Lactobacillus paracasei, PPARG activity is upregulated, and intestinal integrity is restored. Bifidobacteria produce short-chain fatty acids, such as butyrate, which are ligands for PPARs. In turn, PPARG supports maintenance of commensal bacteria such as Candida albicans and Bacteroides fragilis. Consequently, PPARG activates B-defensin-1-mediated immunity, which constitutes another intestinal anti-inflammatory mechanism. Microbiota-activated PPARG-signaling also prevents dysbiotic expansion of pathogenic Escherichia and Salmonella by reducing the bioavailability of respiratory electron acceptors to Enterobacteriaceae in the lumen of the colon. These studies suggest that the normal gut microbiota activates the intestinal PPARG in the maintenance of intestinal mucosal homeostasis.
Antibiotics affect the balance of the gut microbiota but co-administration of plant products can normalize the microbial imbalance by reduced intrusion of pathogens and increased probiotics such as Lactococcus, Lactobacillus, Bacillus, and Pseudomonas. Resveratrol reduces levels of Enterobacteria while improving the availability of Bifidobacteria and Lactobacilli in the DSS-induced colitis rat model.
Another phytochemical, quercetin restores the gut host-microbe relationship, that in turn results in alleviating colitis through rebalancing the anti-inflammatory effects and bactericidal capacity of macrophages. Curcumin is also efficacious in influencing the composition of our gut microbiota and intestinal permeability with suppression of inflammation and oxidative stress.
PPARG has been extensively shown to decrease the expression of TNFa. TNFa is an important cytokine in regulating immune cell function and also acting as a macrophage and neutrophil chemoattractant.
Although this cytokine has an important role in the killing of bacteria, excessive expression unfortunately promotes chronic inflammation results in other poor health effects, such as rapid weight loss. In human neutrophils, TNFa actually increases PPARG mRNA and protein expression, likely as a compensatory mechanism or a feedback loop. THSG, berberine, CAPE, cavidine, CLA, and punicic acid have all shown potential for interfering with TNFa activity and production.
Macrophages can transform to pro-inflammatory (M1) or antiinflammatory (M2) phenotypes in response to invading pathogen. But these deviations are not fully understood.
It is well documented that infective products such as LPS or TH1 cytokines, such as TNFa and IL-6, can polarize macrophages into the pro-inflammatory (M1) pathway, leading to further pro-inflammatory cytokine release which is responsible for the inflammatory cascade that disperses attacking microbes. In contrast, TH2 cytokines such as IL-4 and IL-13 channel the macrophage release towards the M2 pathway, which releases antiinflammatory cytokines involved in tissue repair and remodeling.
Along with TNFa, several ILs are produced in response to inflammatory stimuli. IL-6 is a component of the acute inflammatory response. PPAR agonists were reported to decrease local production of IL-6 in the intestine as well as IL-8 production. IL-8 is a key chemokine for neutrophil trafficking and broadly expressed by a multitude of cell types, including macrophages, and induced by a variety of inflammatory stimuli. IL-1B is also produced to promote acute inflammation and is reduced by PPAR agonists in a PPARG-dependent manner. The broad-ranging effects of PPARG ligands on pro-inflammatory cytokines may be due to PPARG effects on the NFkB pathway, as PPARG has been shown to decrease NFkB expression. Most of the phytochemicals listed in this review have been shown to suppress proinflammatory cytokines and modulate intracellular transduction in inflammatory pathways.
In addition to its effects on NFkB, PPARG activation also inhibits expression of other transcription factors, such as AP-1, activator of transcription (STAT-1), and the expression of adhesion molecules, such as intercellular adhesion molecule 1, as well as the matrix metalloproteinase, MMP-9. During inflammation in UC, PPARG directly regulates expression of pro-inflammatory genes in a ligand-dependent manner, by antagonizing the activities of other transcription factors such as families of NFkB and AP-1.
Title: Re: FAAH Inhibitors
Post by: Physi on June 24, 2021, 12:00:24 PM
Hm. I should not have bought an alcohol-free extract of lungwort (
Extraxt with glycerin, water, lungwort.
I should have bought (tea) leaves like you.

I can't say I feel anything from that extract.
Tried it a few times now in the last weeks.
Maybe I think it gives some feeling that I need to take a deep breath, but this could just be imagination.

Maybe you can elaborate a bit more (except for the chest pain effect it had when taking it first, might be coincidence?).
How does it differ if you take it related to orgasm or not, related to POIS or not?

You just take tea, right? So it's also not the the ethanol extract that you mentioned.

Regarding your question about CBD: Tried it a few times, I think it was nice. But my bottle ran out and I didn't buy a new one because I read it has bad effects on sperm.
If we manage to have a second child, I can finally experiment with more stuff that has bad effect on fertilitity, like Bacopa Monnieri (  :P

I am sorry to hear that lungwort hasn't worked for you so far. I also want to test the extract form you tried, but I can't make a comparison as of yet. Also consider that I usually use about 2 spoonful of leaves with more than 1 liter of hot water. Please note that currently I am not trying to treat myself, but rather to sort out which supplements are beneficial or detrimental, so I move on to something new even when I find something good. Later I will try to combine the beneficial ones, but I bought a lot of other supplements that I want to try out beforehand. I only used lungwort tea a few times, but it was surely beneficial when I had depressive POIS. The benefit of lungwort is that it has quite a rapid effect (1-2 hours), however its effectiveness also vanes quickly so it is a good urgent remedy, but not something to really hold off POIS.

Some other experiences I had:
- Chia seeds: I used about one spoon (2 bigger teaspoon) of chia seed in the morning and one in the evening. I put it in a cup of water and waited 10-15 minutes before consuming it. An effect can be seen in about 6-9 hours. Chia seeds don't have a great impact on depression or POIS symptoms, but they can definitely reduce the burning pain by next day. Stool quality is also much better. By taking chia in the evening and drinking saffron tea in the morning I may finally be able to get rid of coffee entirely.
Chia seeds are considered PPARA agonists, so this may be a reason why it could be beneficial.
- Magnesium [795 mg per pill]: The pure form is also beneficial on stool quality, although I don't think it did anything to the burning pain. I may have misjudged magnesium based on my past experiences, but I still need to test it more. In the past I used combined magnesium and vitamin B6 pills and I think vitamin B6 makes me somehow ill, although probably not in a POIS-like manner.
- Physalis peruviana (inca berry): As far as I could judge it had a good quality. I tested it against an O by consuming 20 pieces 3 hours before O than 20 pieces right after O then 20 pieces again a few hours later but it doesn't look like if it has any great effect. It did nothing to depression and I still had symptoms, although I think it somewhat reduced the bloodshot eyes symptom. I couldn't figure out how it affected the burning pain, so I will need to test it some more. With so little effect it is certainly not a cost-effective treatment for me. Maybe I could try making a tea from the berries and see if it is any better that way.
- Safflower spice (Carthamus tinctorius) which is also referred to as bastard saffron [1 liter tea made with two spoonful of dried safflower stigmas]: I though it could be interesting to test and compare it to saffron. I can conclude that bastard saffron certainly doesn't have any anti-depressive effects like saffron. At least it seems to have weakly reduced the burning pain, so it is not something bad at least. From its seed they also produce oil which I may test later.
- Oregano: I made a tea from the spice I had at home and consumed 7 deciliter of the stuff. It has an interesting and potent taste. I am quite certain that oregano tea induces bloodshot eyes. I slept very poorly that night, but I don't know if it was due to oregano or not. In the next morning the stool quality was better, but the burning pain was present, however I couldn't judge if oregano actually induced it or not, so I need to test it more.
- Papaya pills [papaya leaves and fruit powder – 500 mg per pill]: Papaya pills certainly have a positive effect. I think it has a weak effect on depression and can reduce other symptoms to a weak-moderate level. The problem is that I need to take several pills for a noticeable effect and this doesn't make papaya pills cost-effective as they are not exactly cheap.
- Lavender: I just rechecked what I wrote about lavender tea and realized that I neglected to mention that it has a really good effect on depression. I think this becomes really apparent after about 5 hours and lasts quite long. I think it could be combined well with saffron and lungwort which have a more rapid, but shorter lasting effect. 

By chance I came across something that seemed interesting. In order to restore hormonal balance google recommends lavender, raspberry leaves, tea tree oil and oat straw. Interestingly lavender and tea tree oil are also indicated as disruptors of hormonal balance. Lavender and tea tree oil have an estogenic and an anti-androgenic effect.

As lavender was beneficial I thought I would give a try to the rest as well.
Raspberry leaves (Rubi idaei folium): The tea made from raspberry leaves turned out to have a really positive effect.
It only has a weak effect on depression, but it can definitely ameliorate POIS symptoms. I tested it against an O by drinking the tea before and after ejaculation and it couldn't prevent the occurrence of symptoms, but by next day I can still see a clear difference. Raspberry leaves contain some of the previously mentioned flavanoids, however what seems to be more interesting is that it also contains some phytosterols (B-sitosterol, stigmasterol) as well.
Phytosterols are actually considered as xenoestrogens. Check the bottom of the page for an extensive list of androgen and estrogen receptor modulators.

Tea tree oil [4 drops on a teaspoon of sugar]: I only tried tea tree oil once, but I think it also has a positive effect.
Oat straw is Avena sativa which is actually a component of the combined Echinacea and Avena sativa pills I had some success with. The pills only contained 50 mg Avena sativa, however it is also sold as a standalone supplement with 250 mg of content, so I feel I have to test that as well.

I read most of your post, but I don't remember if you ever had your testosterone or estrogen levels checked. Could it be that vaginal estrogen is the reason why sex with a woman results in less POIS? Does the use of a condom matter in this regard?

I tried testing fenugreek by taking it two hours before an O, however it changed nothing and I was forced to take other effective medication. I am going to test it further to see if it does anything by a longer term use.

Some other background information:
Check out Table 3 for scientifically proven testosterone enhancers!
Table 3. Published evidence showing an increase, decrease or no change in testosterone (T) with supplementation

Chia intake increased HDL cholesterol (HDL-c) and reduced LDL cholesterol (LDL-c) levels. PPARA mRNA expression was elevated, and levels of NF-kB mRNA expression were reduced in the STC group. mRNA expression and protein levels of TNF-a were lower in rats fed the standard diet. Protein levels of IL-1B were reduced in rats fed the standard diet, and the high fat diet with chia.
Chia intake improved antioxidant activity by increasing SOD expression, PPARA expression, catalase activity, and HDL-c levels. In addition, chia consumption decreased the concentrations of the inflammatory markers IL-1B and LDL-c.!divAbstract

Raspberry leaves (Rubi idaei folium) are a source of flavonoids, gallic tannins, phenolcarboxylic acids, sterols, vitamin C and oligoelements (selenium, vanadium). The leaves are not mentioned by the scientific literature for their possible use in metabolic diseases (diabetes, dyslipidaemia, hyperuricaemia), but among their compounds, polyphenols, sterols and vitamin C might be responsible for these properties.
Using HPLC gallic, chlorogenic, caffeic, p-coumaric and ferulic acids, tannin, rutin, quercetin and catechin were identified in young leaves; rutin (0.0540 g%) and p-coumaric acid (0.03174 g%) were also quantified.
According to the scientific literature, raspberry leaves have antioxidant properties, being a source of: 0.46–5% flavonoids (rutin = quercetin-3-O-rutinoside, hyperoside = quercetin-3-O-galactoside, tiliroside = kaempferol-3-O-B-D(6’’E-p-coumaroyl) glucopyranoside and other heterosides of myricetin, kaempferol, quercetin, isorhamnetin); 2.06–6.89% gallic tannins as monomers and polymers (sanguiin H6, lambertianin C), phenolcarboxylic acids = AFC (gallic, chlorogenic, gentisic, ellagic, caffeic, ferulic, lithospermic, p-coumaric acids); sterols (B-sitosterol, stigmasterol); vitamin C and oligoelements (selenium = 19–381 ug/kg, vanadium = 138–1958 ug/kg).
Myricetin acts as a potent inhibitor of xanthinoxidase’s activity and lithospermic acid raises glomerular filtration rate.

Carica papaya is a tropical plant species discovered to contain high amounts of natural antioxidants that can usually be found in their leaves, fruits and seeds. It contains various chemical compounds demonstrate significant antioxidant properties including caffeic acid, myricetin, rutin, quercetin, a-tocopherol, papain, benzyl isothiocyanate (BiTC), and kaempferol. Therefore, it can counteract pro-oxidants via a number of signaling pathways that either promote the expression of antioxidant enzymes or reduce ROS production.
Papain is the most widely exploited proteolytic enzyme from the Carica papaya L. and it has been used to help with meat tenderization and digestion. It is worth to note that papain exhibited great potential as a medication, as it is suggested to exhibit drug-like properties for atherosclerosis and associated conditions, which involve monocyte-platelet aggregate (MPA)-regulated inflammation.
ROS are produced to eliminate invaders whereby activates Nuclear factor kappa-B (NF-kB). NF-kB is a transcription factor and plays a role in inducing inducible nitric oxide synthase (iNOS) activity and, thus, nitric oxide (NO) production. Excessive ROS upregulated prostaglandin E2 (PGE2) synthesis and, hence, cyclooxygenase-2 (COX-2) expression, which eventually leads to oxidative stress that causes tissue damage and worsens inflammation.
Another study further suggested that oxidative stress and inflammation are interrelated as oxidative stress resulting from high ROS can precipitate the formation of inflammation by increasing the gene expression coding for inflammatory proteins, including NF-kB, peroxisome proliferator activator receptor gamma (PPARG), and activator protein 1 (AP-1). Consequently, inflammatory chemokines and cytokines are produced to induce inflammation.
Somanah and co-workers revealed that papaya extracts at a dose of 2 mg/mL showed protective effects through attenuated ROS production and pro-inflammatory cytokines secretion of interleukin-6 (IL-6) and TNF-a as well as upregulating antioxidant enzymes activities. Another in vivo study showed that papaya juice demonstrated anti-obesity properties by reducing obesity markers, inflammation and oxidative stress in high-fat diet rats by upregulating SOD levels, attenuated serum malondialdehyde (MDA), PPARG, lipid peroxidation, and ROS production at a treatment dose of 1 mL per 100 g of body weight.
In addition, a range of phytochemicals with great strength of anti-inflammatory effect, such as benzyl isothiocyanate (BiTC), B-carotene, lycopene, and vitamin C could be found in various parts of papaya fruits, in either pulp or seeds. These phytochemicals were proven to inhibit pro-inflammatory cytokines including TNF-a, IL-6 and monocyte chemoattractant protein-1 (MCP-1).
The further study showed that addition of selenium to the papaya fruit extract synergistically upregulated TGF-B and VEGFA resulting in a significant acceleration in the wound healing process.

@Progecitor thank you for your post.

As I said in my post about physalis, you have to take 20 berries (you can take 25 the first time to be sure) 45min to 65min before O. It is really important to understand that out of that 20 min window they are totally uneffective. That method worked for me at 100% since almost 2 years and some people commented on my original post that it worked 100% for them as well. I strongly believe that it could work for a lot of people but those instructions must be followed exactly.

I've been POIS free for a long time using that method, I still have POIS but those berries, if used correctly, completely blocks the effects. I insist on the fact that it is the only way to use them and that taking them after or not respecting the 45 min to 65 min window makes the treatment totally uneffective.
Title: Re: FAAH Inhibitors
Post by: Progecitor on June 25, 2021, 03:32:37 PM

@Progecitor thank you for your post.

As I said in my post about physalis, you have to take 20 berries (you can take 25 the first time to be sure) 45min to 65min before O. It is really important to understand that out of that 20 min window they are totally uneffective. That method worked for me at 100% since almost 2 years and some people commented on my original post that it worked 100% for them as well. I strongly believe that it could work for a lot of people but those instructions must be followed exactly.

I've been POIS free for a long time using that method, I still have POIS but those berries, if used correctly, completely blocks the effects. I insist on the fact that it is the only way to use them and that taking them after or not respecting the 45 min to 65 min window makes the treatment totally uneffective.

Alright I will, but I have a lot of other more promising supplements I want to test, so it is not a priority right now. It is also possible that we have either a different subtype of POIS or maybe the degree or initiation point of POIS is different. In my case I have a CFS-like POIS as I have symptoms all the time, but symptom deterioration correlates dominantly with an O event. My symptoms begin to rise (e.g. bloodshot eyes) during masturbation even without an O. Likewise practically all effective treatment I have found so far work anytime I take them, although some have a more pronounced protective effect if taken ways before (6-12 hours) an O while others have a more rapid effect and can serve well right after O.
I am glad you have already found some very effective treatment, but you could also contribute to discovering what differentiates these subtypes which may also lead to understanding the underlying mechanism.
I know that many mention that they have tried everything mentioned on the site without any benefit, however they neglect to define what "all" entails which makes me a bit skeptic. I think every POISer should at least test the most indicated treatments and report about them even if they were detrimental. Some of these would be tryptophan, taurine, turmeric, vitamins B, quercetin, niacinamide and some more. In my case the most effective ones so far were alfalfa (aka lucerne), MACA, saffron, Ashwagandha and these were effective for others as well. Pharmaceutic drugs could be problematic as some of them have to be prescribed, however paracetamol and some antihistamines could be easily tested.
Of course it all depends on you if you are willing to try any of these, however you could also potentially find something that works at least as well or maybe even better than physalis or at least not so time-dependent if you miss the interval.

You also mentioned you want to uncover which of the components of Physalis are beneficial.
Hopeoneday and Muon have already pointed out promising compounds. By using google and wikipedia it is really easy to find information on them. This way one can find foods and supplements abundant in these compounds. I have collected some to make this easier and I plan to test them as well, however I am only one case of POIS and thus I can't represent every POISer.

By finding of active copmponent  here could be cruciall to found marker for pois.


    Phytosterols, which may act as antioxidants [1]
    Linoleic acid, which may also as an antioxidant [1]
    Oleic acid [1]
    Palmitic and stearic acid [1]
    Tocopherols, which may have antioxidant activity and act as a source
    of vitamin E [1]
    Beta-Carotene, which is a source of vitamin A [1]
    Vitamin K [2]
    Withanolides, which are a group of naturally occurring steroids that may have anti-inflammatory effects [2]


- Some phytosterols:
Campesterol: abundant in canola and corn oils
Stigmasterol can be found in soybean and rape seed.
Beta-sitosterol can be found in a variety of vegetable oils, nuts and avocados.
Recently I had some success with the tea of raspberry leaves which also contains stigmasterol and beta-sitosterol.
- Linoleic acid is abundant in safflower oil, evening primrose oil, melon seed oil, poppyseed oil, grape seed oil, sunflower oil.
Actually I am a bit suspicious of linoleic acid in relation to my case, but I need to test more before I can confirm anything.
- Oleic acid can be found in olive oil, avocado and almond oil.
- Palmitic acid is a major component of palm oil, stearic acid can be found mainly in animal fat, but cocoa butter and shea butter are also rich in it.
- There are supplements which combine DEKA vitamins.
- Withanolides can be found in Ashwagandha (Withania somnifera) as a matter of fact.

Physalis also contains rutin, myricetin, quercetin and kaempferol. Rutin, myricetin and quercetin can be bought as standalone supplements.  A higher level of kaempferol can be found in galangal.
Title: Re: FAAH Inhibitors
Post by: Progecitor on July 05, 2021, 10:38:22 AM
Ecdysterone is very good! See the other post:

Fenugreek powder: So at first I took one teaspoon (about 4 g) of fenugreek mixed in some water, then had an O five hours later with a weak-average POIS onset.  One hour later I took another teaspoon of fenugreek, however in the following hours my POIS symptoms still became a bit worse (bloodshot eyes). Four and a half hours later I took another teaspoon of fenugreek then another four and a half hour later a last teaspoon of fenugreek before going to sleep. So all in all I took 4 teaspoon of fenugreek which may equal to about 16 gramms. During the day I couldn't find a change in depression, although it was weak. The bloodshot eyes were quite average and the breast lymph nodes were present without noticeable change. Fenugreek also caused more than average flatulence. In the morning the urine had a reduced burning sensation. The stool was looser and the burning sensation was reduced. In the morning I also took another teaspoon of fenugreek, but I also needed to take a MACA capsule as the eyes were quite bloodshot. During work I felt quite weak and the muscle fatigue was noticeably present. So to sum it up fenugreek didn't prove to be of much help, but at least it doesn't make things worse either.

Anise tea [about 1 liter]: As it is another estrogen receptor modulator I thought it could be interesting to test. It doesn't seem like it does anything particular to my POIS symptoms, however it can give me a headache when I drink too much. Could this be something similar as what I had experienced with Kudzu?

Galega/goat's-rue/French lilac tea (Galega officinalis) [about 1 liter]: It raised my interest as it is another traditional antidiabetic tea and it contains some compounds that formed the basis for the development for metformin. I expected it to potentially modulate POIS, however this proved to be in vain. It seems to have some beneficial effect on POIS, however this effect is quite subdued. Now I have to wonder what metformin would actually do.

CLA / conjugated linoleic acid [2000 mg per gelcapsule (80% FFA)]: I took 2-3 capsules for two days. It has some effect on POIS, but its quality seems to be mixed and weak, so it doesn't really do anything to symptoms or only weakly enhances POIS. Nevertheless it is not a supplement I plan to incorporate in my regime.

Evening primrose oil [500 mg per gelcapsule of which 45 mg is gamma-linolenic acid]: It has mixed effects just like CLA. I took three-four capsules in a day for two days. Although primrose oil can reduce the burning pain, it doesn't make a real difference when I begin to masturbate. It also induces bloodshot eyes almost every time I take it, which is a no good for me. The nodules in the breast didn't seem to change, although it is indicated as a possible treatment for breast pain.

Ayurveda tea: The most indicated ingredients are Withania somnifera and Centella asiatica, but it also contains cymbopogon citratus, glycyrrhiza glabra, pterocarpus marsupium, zingeber officinale, ocimum sanctum, cinnamomum tamala, cinnamomum zeylanicum. I had some negative experience with it. I only drank it three times, but as I remember it gave me a headache every time. I even developed a serious chest inflammation after one occasion, although it was possibly not due to the tea. Due to this I was a bit skeptical about Ashwagandha and Gotu Kola.

Garlic pills [10 mg per gelcapsule]: I took garlic capsules from the morning with 3-4 hours of difference. It definitely reduces the burning feeling moderately. After taking the third I had an O two and a half hour later, after which I took another garlic capsule and three hours later a last one before going to sleep. When I got up in the middle of the night to take a leak I also took a garlic capsule. This way garlic couldn't definitely prevent POIS as I still had bloodshot eyes, however besides the reduced burning sensation I had reduced rhinitis. In the morning I felt that I had more energy. So garlic is definitely helpful, however on its own it is not an adequate treatment.

Ashwagandha (Withania somnifera) [240 mg per capsule of which 12 mg is Withanolid]: I took one capsule in the morning and one another five hours later. I took a third one six hours later and had an O two and a half hours after that. To my wonder this partially managed to prevent POIS onset as I didn't really develop bloodshot eyes and the burning sensation was also reduced. In the morning I had a somewhat reduced fatigue and depression, however I had bloodshot eyes and the burning pain was moderate. After testing it some more I realize that at first I overestimated Ashwagandha's benefit as it didn't prove to be that effective on acute days. At best it may be as good as berberine, however I need to take at least four capsules for this and there could be adverse side-effects if I used such an amount regularly.

Gotu Kola (Centella asiatica aerial parts) [435 mg per capsule]: Another suspicious one that proved to the contrary. I took one in the morning then another in the afternoon and a third one in the evening after which I had an O one hour later. I didn't develop bloodshot eyes right after O, but I had some cramping intestinal pain. In the morning I generally felt somewhat better, than I would usually expect, however I still had a moderate burning pain and thus POIS symptoms as well.

Actually I can't even tell which was the more beneficial, but garlic pills, Ashwagandha and Gotu Kola at least have some benefit and deserve further testing. I also had a weak heartburn with either Ashwagandha or Gotu Kola, but I forgot to note it and I can't clearly remember.

Further information on some supplements:
Major constituents of anise essential oil are anethole, gamma-himachalene, cis-isoeugenol and linalool. It seems that among the compounds of anise oil, anethole has the most important role in treatment of migraine attacks. Because anethole has a similar structure to dopamine, so it is possible that anethole acts as an antagonist of dopamine in binding to the dopamine receptor. Due to the role of dopamine in inducing migraine attacks, it is proposed that the use of a dopamine antagonist could also block the chain of migraine attack cascade.
Since the plasma levels of GABA during migraine attack is not detectable, but after this phase, its level increases, one of the hypotheses proposed to stop the migraine attacks is activation of GABA pathway. Considering previous studies that reported that anise oil may cause activation of GABA receptors, GABA pathway activation may be another mechanism of action of anise oil.
Other compounds of Anise oil, such as eugenol and estragole, also have anesthetic, muscle relaxant and anti-epileptic properties which could help relieve migraine headaches.
Moreover, analgesic effect of Anise essential oil was reported similar to morphine and aspirin. Also, the findings demonstrated that the anise oil has anti-inflammatory effect as strong as indomethacin and has analgesic effect comparable to that of 100 mg/kg aspirin and 10 mg/kg morphine.

Saturated fatty acid esters may cause mastalgia (breast pain) via hypersensitivity of breast epithelium to circulating hormones. Evening primrose oil (EPO) may restore the saturated/unsaturated fatty acid balance and decrease sensitivity to steroidal hormones or prolactin. Conflicting results exist regarding EPO treatment for mastalgia.
The therapeutic efficacy of EPO on mastalgia was significantly higher than with paracetamol. Factors significantly affecting the efficacy of EPO treatment were hormone replacement therapy (HRT), IUD-with-levonorgestrel, iron deficiency, overt hypothyroidism, and Hashimoto thyroiditis. Replacement of iron or thyroid hormone efficiently treated mastalgia in patients that did not respond to EPO treatment. Side effects (allergy, anxiety, blurred vision, constipation, and nausea) were rare and not statistically significant.

Background and Aim: Polycystic ovary syndrome (PCOS) is one of the most important reproductive and endocrine disorders in women. Evening primrose oil is a phytosterogenic plants, and there are many reports about the effects of phytoestrogens on the hypothalamus-pituitary axis.
30 female Sprague Dawley rats with regular sexual cycle were divided into five groups. Group 1: control. Group 2: (control treatment) received evening primrose oil gavage at dose of 1000mg/kg for 21 days. Group 3: PCOS induced by estradiol valerate. Group 4: After induction of PCOS received evening primrose oil gavage at dose of 1000mg/kg for 21 days. Group 5: After induction of PCOS received evening primrose oil gavage at dose of 2000mg/kg for 21 days.
Results: The FSH level increased significantly in the fourth and fifth groups compared to the third. Levels of LH and testosterone levels were significantly lower in the fourth and fifth groups than the third group. There was no significant difference in the level of FSH and LH among the other groups.
Conclusions: By changing the concentration of FSH, LH and testosterone hormones in polycystic ovary syndrome, evening primrose oil, can reduce the complications of these hormonal changes. EPO also reduces insulin and serum glucose and increases insulin sensitivity in PCOS. With more complete studies, Evening primrose oil can be recommended as a good alternative to chemical drugs for the treatment of PCOS.

Ashwagandha (Withania somnifera), also known as Indian ginseng and Winter cherry, belongs to the solanaceae family. In Sanskrit, Ashwagandha means odor of the horse, originating from the "odor of its roots" which resembles to that of a sweaty horse. The name "somnifera" in Latin means "sleep-inducer" which refers to its extensive use as a remedy against stress from a variety of daily chores.
The major biologically active constituents from various parts of Ashwagandha are steroidal alkaloids and lactones, a class of chemicals known as withanolides.
In experimental model of swimming endurance test, a forced swimming behavioral paradigm to model exhaustive physical exercise in rats, it has been shown to increase their stamina, and prevented adrenal gland changes of ascorbic acid and cortisol content produced by swimming stress. In experimental models of neurodegenerative disorders like Alzheimer's (AD) and Parkinson's disease (PD) in which functional impairment is primarily caused due to disruption of neural network and premature death of neurons, Ashwagandha-derived crude extracts and isolated active components
displayed good therapeutic potential that included formation of dendrites and induction of sleep and relaxation similar to GABA (amino acid and neurotransmitter). Ashwagandha root extracts exhibited neuroregenerative property in AB-induced in vitro and mouse model of AD. Interestingly, it also stimulated neurite growth and enhanced memory function in normal mice.
Molecular investigations by some other workers revealed that the active components of Ashwagandha target amyloid precursor protein (APP) cleaving enzymes for reversal of AD pathology. Sominone, on the other hand, has been shown to activate RET, part of the receptor complex for glial cell line-derived
neurotrophic factor (GDNF), to stimulate axonal growth. Recovery potential of the extract was attributed to increase in the expression of PPARG, reduced by AB1-42.
Ashwagandha root extracts have also proven beneficial to protect neuronal injury in vitro as well as animal models of PD. Pre-treatment with Ashwagandha extracts was found to prevent alterations in anti-oxidant enzyme activities, catecholamine content, dopaminergic D2 receptor binding and tyrosine hydroxylase expression in 6-hydroxydopamine-induced rodent models of PD.
Investigation of molecular markers revealed that the extract significantly reduced the expression of iNOS, an established measure of oxidative stress.
Supplementation of Withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and apoptotic cells in hippocampus.
Moreover, Withanolide A increased glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone-dependent manner.
The pre-treatment of water extract of Ashwagandha leaves (WEX) extract markedly inhibited glutamate-induced cell death and HSP70 expression.
Water extract of Ashwagandha leaves showed protection against lead-induced neurotoxicity. Furthermore, the i-Extract and WEX of Ashwagandha leaves caused protection against oxidative stress and glutamate toxicity.

The four main triterpenoids occurring in Centella asiatica were shown to attenuate colitis in mice by oral administration. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORGt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Furthermore, madecassic acid was identified as a PPARG agonist, as it promoted PPARG transactivation. The correlation between activation of PPARG and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARG/AMPK/ACC1 pathway.
Accumulative evidence suggests that nuclear receptors, especially peroxisome proliferator-activated receptor gamma (PPARG), has a vital role in regulating Th17/Treg balance. The PPARG agonists inhibit Th17 cell differentiation in lung myeloid dendritic cells and promote Treg cell differentiation in the white adipose tissue of mice. Meanwhile, various pentacyclic triterpenes were reported to activate PPARG. These findings suggested that the triterpenes in C. asiatica might restore the Th17/Treg balance through the PPARG pathway.
PPARG, a ligand-dependent nuclear receptor that has vital roles in adipogenesis, glucose metabolism and immune modulation, is highly expressed in the colon. Intensive preclinical studies have highlighted that the activation of PPARG conferred protection against colitis in mice. Madecassic acid was shown to activate AMPK in a PPARG-dependent manner and induce the AMPK/ACC1-mediated shift of Th17 toward Treg cells by activating PPARG. In contrast, inhibition or depletion of AMPK did not inhibit madecassic acid-induced translocation of PPARG into the nucleus. The findings suggested that AMPK might be a downstream effector of PPARG.
There are many reports which indicate that high-affinity synthetic ligands of PPARG, such as thiazolidinediones, have immunoprotective roles in experimental colitis. Similar to rosiglitazone, madecassic acid promoted the expression of PPARG-responsive genes CD36 and LPL, induced PPARG translocation from cytoplasm to nucleus and the binding of PPARG to a reporter gene, which could be diminished by PPARG antagonists or PPARG siRNA.
Title: Re: FAAH Inhibitors
Post by: Progecitor on July 08, 2021, 12:16:32 AM
Additional information on possible herbal remedies for sexual disorders.

As a result of Bulgarian research, Tribulus has become a popular herb for the treatment of female and male endocrine disorders. It is considered a general tonic, aphrodisiac, estrogen, and androgenic modulator, and is used to restore vitality, libido, and reduce the physiologic effects of stress. Bulgarian research has identified a steroidal saponin known as a furostanol saponin, calculated to no less than 45% protodioscin. The leaf is noted to be higher in the unique saponin rather than the fruit. Other active constituents include phytosterols and spirostanol glycosides. The tonic activities are exacted through intensifying protein synthesis and enhancing the activity of enzymes associated with energy metabolism. Protodioscin, a steroidal saponin in Tribulus, has been proven to improve sexual desire via the conversion of protodioscine to DHEA (dehydroepiandrosterone).

Infertility, male
Botanical medicines
Panax ginseng (Chinese or Korean ginseng): Panax is effective in male infertility. Panax promotes growth of testes, increases sperm formation and testosterone levels, and increases sexual activity and mating behavior in studies with animals. Panax enhances nitric oxide production, which helps regulate capacitating process of sperm and acrosome reaction. Thus Panax improves fertilization sperm motility. Ginsenosides influence hypothalamic-pituitary-testicular axis, modulating stress-induced infertility or lowered testosterone from insufficient dehydroepiandrosterone (DHEA) synthesis. Panax may increase testosterone levels and sperm counts. Panax can be used for oligospermia, even with varicocele, and for improvement of erection and libido.

Pygeum africanum: improves fertility if diminished prostatic secretion plays significant role. It increases prostatic secretions and improves composition of seminal fluid by increasing total seminal fluid, alkaline phosphatase, and protein. It is most effective if alkaline phosphatase activity is reduced (<400 IU/cm3) with no evidence of inflammation or infection (no white blood cells or immunoglobulin A [IgA]). Lack of IgA in semen is a good indicator of potential clinical success. It improves capacity to achieve erection in patients with benign prostatic hypertrophy or prostatitis as determined by nocturnal penile tumescence. (Benign prostatic hypertrophy and prostatitis often are linked to erectile dysfunction and other sexual disturbances.)

Tribulus terrestris: Ayurvedic tonic and aphrodisiac; used in European folk medicine to increase sexual potency. Chief constituent: protodioscin, a steroidal saponin. Correct sourcing of Tribulus is critical to ensure its effectiveness. All scientific data and clinical outcomes are based on a leaf extract from Bulgaria, highest in protodioscin. Sources form other nations or plant parts may be less effective. In animal studies, Tribulus increased sex hormones (e.g., testosterone) and improved nitric oxide synthesis; however, these results have not been observed in some human studies. Explanation: differences in extract and plant parts and the fact that studies included healthy males with normal testosterone. Tribulus enhances male fertility by increasing sperm count, viability, and libido; however, study results are unclear.

Astragalus membranaceus: increases motility of sperm in semen. Astragalus increases motility of sperm in semen and motility of washed sperm, relevant to those seeking ART treatment.

Turnera diffusa (damiana): traditionally used for "its positive aphrodisiac effects, acting energetically on the genitourinary organs of both genders where it was highly indicated for sexual weakness and debility." It is a stimulant tonic of sexual organs, especially during "enfeeblement of the central nervous system." It is especially beneficial for sexual debility, erectile difficulty, and depression. Human studies are lacking. In male rats: damiana facilitates sexual behavior in rats with sexual dysfunction, reduces ejaculation latency, produces a restorative effect in sexual exhaustion, and hastens recovery. It suppresses aromatase activity, perhaps increasing levels of testosterone.

Mucuna pruriens (velvet bean): Ayurvedic medicine for endurance against stress, resistance against infection, retardation of aging process, and improvement of male sexual function; it alleviates psychogenic impotence and unexplained infertility. M. pruriens seed powder helps fight stress-mediated poor semen quality. It is a restorative and invigorating tonic and aphrodisiac in infertile subjects. Mechanism: regulation of steroidogenesis and resulting improvements in semen quality. It improves testosterone, luteinizing hormone (LH), dopamine, adrenaline, and noradrenaline levels in infertile men and reduces FSH and prolactin (PRL). Sperm count and motility were also improved in infertile men.

Withania somnifera (Withania): has antistress and adaptogenic effects. At a dose of 5 g powdered root daily, Withania inhibited lipid peroxidation and improved sperm count and motility. It increased serum testosterone and LH and reduced follicle FSH and PRL, all beneficial effects in infertile men.
Title: Re: FAAH Inhibitors
Post by: berlin1984 on July 08, 2021, 02:07:01 AM
I'm 100% with the idea of checking traditional herbs or methods for treatment/management of POIS.

In contrast to the "civilization diseases" brought by our current way of eating and living, I think POIS must be an ancient thing.
Sex drive was always there in males, so tendency to get dysfunctions there from overmasturbation or from pathogens must always have been there (IMHO)
Title: Re: FAAH Inhibitors
Post by: Progecitor on July 30, 2021, 11:35:12 AM
As other POIS cases may be connected to abnormal 5a-reductase or 11B-HSD1 activity a possible role for AKR1C3 (17B-HSD5) still cannot be ruled out. However it is still not clear whether it is really involved in my case or not. Of course the main lead for AKR1C3 is alfalfa/lucerne which contains a good amount of coumestrol which is a very potent inhibitor of AKR1C3.
It also seems controversial that AKR1C3 inhibition would be beneficial, as it should theoretically lower testosterone level, which has yet to be explained.
Interestingly berberine is a potent AKR1C3 inhibitor and it had already proved useful. I also tried Naproxen in the meanwhile, but it only has a weak beneficial effect. Linoleic and arachidonic acid are also inhibitors of AKR1C3, however their in vivo effectiveness may be lower than otherwise measured.
I think testing Brazilian propolis could be a good idea as it is commercially available and it contains baccharin which is a potent AKR1C3 inhibitor.
The red clover supplement also proved to be somewhat beneficial, although only weakly. Red clover also contains a considerable amount of biochanin A which was indicated earlier as a good AKR1C3 inhibitor. Biochanin A is also metabolized to genistein in the body and genistein besides being a FAAH inhibitor is also an aromatase inhibitor.
Furthermore another unexpected finding is that AKR1C3 has a connection to TMPRSS2 which is an important pathogenic factor in COVID-19 infection. It is hypothesized that AKR1C3 is upregulated by TMPRSS2-ERG induction. Although the virus itself doesn't seem to upregulate TMPRSS2, however a high expression facilitates virus entry. Overexpressed AKR1C3 plays a role in several metabolic diseases.
Of course this relation is highly speculative, but recently it was proposed that indomethacin could be beneficial in the treatment of the infection. An earlier article in the thread also proposed a possible benefit for arachidonic acid supplementation. Another highly circumstantial evidence is that I took note of a woman on TV a few months ago when she mentioned that during the infection Naproxen proved to be the most beneficial for her. It is true though that indomethacin, naproxen and arachidonic acid in themselves are involved in cyclooxygenase activity and prostaglandin metabolism, so it is difficult to draw a firm conclusion.

Human aldo-keto reductase family 1 member C3 (AKR1C3) is known as a hormone activity regulator and prostaglandin F (PGF) synthase that regulates the occupancy of hormone receptors and cell proliferation. Due to the overexpression in metabolic diseases and various hormone-dependent and -independent carcinomas, as well as the emergence of clinical drug resistance, an increasing number of studies have investigated AKR1C3 inhibitors.
These enzymes can use a wide variety of substrates, including endogenous steroids, prostaglandins and exogenous compounds. AKR1C enzymes participate in oxidoreduction reactions. However, by exhibiting a higher affinity for NADPH, AKR1C3 primarily performs its reductive activity in vivo. AKR1C1 and AKR1C2 are widely expressed in various tissue types; AKR1C3 shows endocrine organ expression (prostate, adrenals, breast, and uterus), and is involved in the de novo biosynthesis of steroids in the adrenal gland and tumors; and AKR1C4 is specific to the liver and is involved in the synthesis of bile acids.
AKR1C1 facilitates progesterone inactivation and predominantly functions as a 20-ketosteroid reductase. AKR1C2 facilitates potent androgen 5a-DHT inactivation and predominantly functions as a 3-ketosteroid reductase. AKR1C4 has the most robust catalytic efficiency with respect to the formation of 5a/5B-tetrahydrosteroids. AKR1C3 (also known as 17B-HSD5) predominantly functions as a 17-ketoreductase and converts d4-androstene-3,17-dione and 5a-androstane-3,17-dione to testosterone and 5a-DHT, respectively.
It is worth mentioning that only AKR1C3 catalyzes the reduction of d4-androstene-3,17-dione to testosterone. Furthermore, AKR1C3 regulates the ligands of estrogen receptors by converting estrone (a weak estrogen) to 17B-estradiol (a potent estrogen). In addition, AKR1C3 also converts progesterone to 20a-hydroxyprogesterone to alter the ligand affinity for progesterone receptors. Notably, in the prostate, AKR1C2 and AKR1C3 have completely opposite catalytic functions in 5a-DHT activation. When targeting specific diseases, highly selective AKR1C3 inhibitors have numerous merits. Inhibition of the activity of AKR1C2 in prostate cancer (PC) can promote proliferative signaling in the prostate, while inhibition of AKR1C3 can achieve excellent results in the treatment of prostate carcinoma. Thus, selective AKR1C3 inhibitory agents are urgently needed to treat castration-resistant prostate cancer (CRPC) to reduce the unexpected impact of inhibiting other isoforms.
Similarly, AKR1C3 plays a regulatory role in cell proliferation and differentiation in a hormone-independent manner. AKR1C3 functions as a prostaglandin (PG)F2 synthase, catalyzing the conversion of prostaglandin D2 (PGD2) to 9a,11B-PGF2a and reducing the conversion of prostaglandin H2 (PGH2) to PGF2a.
Both 9a,11B-PGF2a and PGF2a act on the PGF receptor and promote cell proliferation by stimulating the mitogen activated protein kinase (MAPK) cascade signaling pathway.
When not metabolized to PGF2a, PGD2 is nonenzymatically converted to PGJ2 and then gradually converted to 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), a putative agonist for peroxisome proliferator-activated receptor (PPARG) and an inhibitor of nuclear factor kappa-B (NF-kB) signaling. Thus, AKR1C3-mediated depletion of PGD2 prevents the formation of anti-proliferating 15d-PGJ2, indirectly blocking cell differentiation. In summary, AKR1C3 plays a crucial role as a PGF2 synthase that regulates cell proliferation in a hormone-independent manner.
Malignant cells can become radioresistant by upregulating AKR1C3 expression to eliminate reactive
oxygen species (ROS), accumulate PGF2a for further activation of the MAPK pathway, inhibit G2/M phase arrest or decrease cell apoptosis.
AKR1C3 is the major enzyme involved in the production of testosterone, an aromatase substrate, in breast cancer cells. The inhibition of AKR1C3 affects the synthesis of estrogen and the occupancy of estrogen receptors. Meanwhile, due to the high specificity of AKR1C3 expression in tumor cells, specific AKR1C3 inhibitors possess an unparalleled advantage over common estrogen receptor antagonists or aromatase inhibitors in regulating estrogen receptor (ER) occupancy. Regarding AKR1C3 as a potential therapeutic target in ER-positive breast cancer, AKR1C3 inhibitors can further block the transmission of estrogen signaling. Additionally, by inhibiting the PGF2 synthase activity of AKR1C3, cell proliferation can be suppressed through a nonhormone-mediated mechanism.
AKR1C3 is distributed in the prostate and regulates androgen levels. This enzyme is involved in all pathways (canonical, alternative and backdoor pathway) associated with testosterone (T) and 5a-DHT production, and the inhibition of AKR1C3 avoids interfering with glucocorticoid synthesis. Furthermore, as a PGF synthase, AKR1C3 suppresses the generation of anti-proliferative 15-deoxy-delta-12, 14-PGJ2. Thus, inhibition of AKR1C3 can be used as a hormone-independent means of controlling the androgen level and growth rate of tumors. The inhibition of AKR1C3 also prevents its ability to co-activate AR, allowing for a more inhibition of adaptive androgen biosynthesis and androgen receptor signaling.
A combination of 3a-oxidoreductase, steroid 5a-reductase type 1 (SDR5A1) and CYP17A1 inhibition can achieve the greatest disruption of DHT production, bringing a new approach to surmount PC recurrence.
Powell and colleagues proposed that TMPRSS2-ERG plays an important role in regulating the expression of AKR1C3. In TMPRSS2-ERG fusion-positive prostate cells, AKR1C3 is upregulated by TMPRSS2-ERG induction. Furthermore, the production of 5a-DHT reduced by the 5a-androstanedione pathway is increased in these cells, driving the activation of AR. In addition, the ERG transcription factor may override the inhibitory effect of AR on AKR1C3 expression.
Recently, Xia et al. proposed a potential mechanism for the continued progression of PC after androgen deprivation therapy. This study described the colocalization of AKR1C3 and type A gamma-aminobutyric acid receptor (GABAAR) in human primary PC specimens, while noting the potential impact of alternative steroid metabolism on disease progression. In their study, the allosteric activator of GABAAR 5a-androstane3a, 17B-diol (3a-diol) promoted the AR-independent PC process by activating a growth factor-dependent pathway, while the GABAAR antagonist could reverse the effect of 3a-diol in promoting cell proliferation.
Furthermore, AKR1C3 plays an essential role in the differentiation, proliferation and apoptosis of hematological malignant cells, with inhibition of AKR1C3 leading to increased levels of PGD2 and 15-deoxy-d12,14-PGJ2.
PGD2 can synergize with all-trans retinoic acid (ATRA) to promote the differentiation and apoptosis of cells, and 15-deoxy-d12,14-PGJ2 will promote the progression of differentiation. It is worth noting that the administration of AKR1C3 inhibitors reduces toxicity and improves bioavailability compared to direct administration of PGJ2 and 5d-PGJ2.
In addition to cancer, AKR1C3 is also closely associated with metabolic diseases.
Endometriosis is a common inflammatory gynecological disease for which there is currently no effective treatment regimen. Normal endometrial epithelium proliferation and maintenance relies on coordinated interactions between estrogen and progesterone, where progestogen can antagonize estrogen-activated cell proliferation by inducing the expression of 17B-hydroxysteroid dehydrogenase type 2 (17B-HSD2). The imbalance of hormonal signals leads to endometrial cancer cell proliferation, endometriosis and dysmenorrhea. At present, the therapeutic drugs for endometriosis primarily target aromatase and gonadotropin-releasing hormone (GnRH) receptor AKR1C3 can locally regulate steroid metabolism in the endometrium without affecting the level of systemic hormones. AKR1C3 mediates the process of progesterone reduction and 17B-estradiol production. The testosterone provided by AKR1C3 is then used as a substrate by aromatase and converted into estradiol. The above metabolic processes lead to the downregulation of progesterone signaling and the upregulation of estrogen signaling. It is also worth mentioning that AKR1C1 predominantly works as a 20-ketosteroid reductase and mediates progesterone inactivation. AKR1C1 inhibition can block such conversion and cause progestational effects. Endometrial damage occurs when progesterone is not able to counteract the estrogenic effects. AKR1C3 regulates endometrial cell inflammation, proliferation and angiogenesis through its PGF synthase activity. It also controls local T and estradiol concentrations and regulates isoprenyl aldehyde and retinaldehyde levels in endometriosis to influence cell proliferation by activating retinoid X receptor (RXR)/retinoic acid receptors (RAR).
Clinically, AKR1C3 has been demonstrated to be an upregulated steroidogenic enzyme in CRPC patients. Liu et al. have demonstrated that indomethacin (22-fold inhibition preference for AKR1C3 versus AKR1C2) reversed the resistance of PC cells to Abi and ENZ in vivo and in vitro.
AKR1C3 converts androstenedione and 5a-androstanedione to testosterone and DHT, respectively, which Abi cannot inhibit. Sustained androgen production is a crucial mechanism for drug resistance. In addition, AKR1C3 overexpression drives drug resistance by enhancing androgen signaling.
By analyzing relevant downstream proteins, they noted that AKR1C3-mediated DOX resistance was associated with the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway.
Chewchuk et al. presented evidence that breast cancer cell DOX-resistance may be caused by the synergistic effect of AKR overexpression and decreased estrogen dependent expression of bcl-2 and cyclin D1.
In addition, owing to AKR1C3 being associated with the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, which responds to oxidative stress, reducing oxidative stress can also decrease tumorigenesis.
Baccharin is a natural ingredient in Brazilian propolis, and unsubstituted baccharin shows strong AKR1C3 preference and inhibitory potency (IC50 = 110 nM).
Among the nine phenolic analogs tested, octyl gallate (OG) and the potent AKR1B10 inhibitor caffeic acid phenethyl ester (CAPE) show potent inhibitory effects toward AKR1C3.
Another alkaloid, berberine (BBR), was screen from a traditional Chinese medicine monomer library. Intriguingly, reports have shown that BBR has a better inhibition potency than indomethacin (IC50 = 7.26 uM).
This activity may be due to BBR inhibiting cell proliferation in two ways (as an AR antagonist and by blocking intratumoral steroidogenesis) and the additional hydrophobic interaction with the SP2 pocket amino acid residue.
It is noteworthy that ruthenium complex, which is not associated with a condensed benzene ring in the ligand, shows multiple binding to AKR1C3 and exhibits selective inhibitory activity against AKR1C3 (Ki = 560 nM). Several Ru complexes cause quasi-irreversible inhibition of AKR1C enzymes (binding to the peripheral site). Most of these Ru complexes show a preference for inhibiting AKR1C1 and AKR1C3.
Glimepiride (GLM, a the third-generation anti-diabetes drug, is a potent and selective in vitro AKR1C3 inhibitor. Another sulphonylurea that moderately inhibits AKR1C3 (IC50 = 19.62 +/- 1.67 uM) is the first/second-generation anti-diabetes drug gliclazide (GLC).
Some long-chain polyunsaturated fatty acids exert potent competitive inhibition toward AKR1C3. Linoleic and arachidonic acid produce a similar degree of potent inhibition of both common substrates (S-tetraol and PQ) of AKR1C3 in vitro. However, due to the metabolism of fatty acids and the high binding rate of albumin, their inhibitory activity against AKR1C3 recombinant protein is much lower than that observed under intracellular conditions. However, linoleic acid still affects cellular PQ metabolism by inhibiting AKR1C3 in a dose-dependent manner.
Jasmonic acid is poorly selective for the AKR1C family due to its cyclopentane side chain moiety being too short, allowing it to be accommodated to all AKR1C enzymes. The inhibitory activity of methyl jasmonate toward AKR1C3 (Ki = 153 +/- 28 uM) was determined when the substrate was PQ.
Naproxen blocks cyclooxygenase-mediated inflammation and inhibits AKR1C3 and AKR1C2.
Indomethacin exhibits AKR1C3 inhibition much more potently than AKR1C1 and AKR1C2. Interestingly, indomethacin binding is influenced by pH.
Since AKR1C1 and AKR1C2 mediate inactivation of the potent androgen 5a-DHT, when targeting CRPC, pan AKR1C enzyme inhibitors can have conflicting and detrimental pharmacological effects.
For those AKR1C3 inhibitors obtained by structural modification of NSAIDs, it is essential to avoid the inhibition of COX enzymes to reduce the incidence of gastrointestinal side effects while effectively inhibiting AKR1C3 activity.
With respect to evaluating AKR1C3 activity, AKR1C3 has two catalytic mechanisms for oxidation and reduction of the substrate. However, in most in vitro studies, researchers have only determined the single mechanism (oxidation/reduction) of inhibitory activity of the compounds against AKR1C3. The choice of oxidation/reduction substrate, reaction buffer system, and test methods used in the activity test are not all the same. At present, the evaluation of the activity of inhibitors is primarily at the target level. Additionally, by exhibiting higher affinity for nicotinamide adenine dinucleotide phosphate (NADPH), AKR1C3 primarily has reductive activity in vivo.
AKR1C3 can not only give rise to strong androgen acting AR receptors to promote the further development of CRPC, it can also induce PC cell proliferation by functioning as a prostaglandin F synthase.
The expression of AKR1C3 is also related to ROS production. Therefore, coregulation of AKR1C3 with oxidative stress signaling pathway Nrf2/antioxidant response element (ARE) genes may depress the incidence of tumors and drug resistance by reducing reactive oxygen species production.

Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the TMPRSS2 gene. This gene encodes a protein that belongs to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The biological function of this gene is unknown.
TMPRSS2-ERG fusion gene is the most frequent, present in 40 - 80% of prostate cancers in humans. ERG overexpression contributes to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling.
Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors."SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option." One experimental candidate as a TMPRSS2 inhibitor for potential use against both influenza and coronavirus infections in general, including those prior to the advent of COVID-19, is the OTC (in most countries) mucolytic cough medicine bromhexine, which is also being investigated as a possible treatment for COVID-19 itself as well.

Based on virtual docking geniposide is possibly a potent inhibitor of TMPRSS2. Geniposide can be found in Gardenia jasminoides fruits, which is also called Cape Jasmine, Zhi Zi or Chija.

Most interestingly crocin and crocetin can also be found in gardenia fruits and therefore it is used as a saffron substitute. Traditional Chinese medicine used the leaves, fruits and flowers of gardenia as a remedy for the common cold. Needless to say this makes it a very interesting thing to try, however I can't find any place in my country that sells it. Later I may still try to order some from abroad, but in the meanwhile others could be interested, especially if they are worried about COVID-19 infection.

Gardenia was also mentioned alongside saffron on the CFS site.
Title: Re: FAAH Inhibitors
Post by: Progecitor on August 03, 2021, 03:30:06 PM
I have updated my summary with several new items that I had tested. It doesn't appear among the recent posts, but I thought some would be interested. I found that Mexican wild yam root is another potentially useful POIS remedy. Scroll down to the bottom and check the green text for details.
Title: Re: FAAH Inhibitors
Post by: Progecitor on August 05, 2021, 09:32:08 AM
As a local hormonal imbalance is a likely cause of POIS the hydroxysteroid dehydrogenases (HSDs) deserve further attention. There is a really good summary table about 17B-HSDs on wikipedia. Many of these enzymes can be found in the prostate, testis and adrenals. Given this it is easy to imagine that any malfunction in them could greatly upset local hormonal balance and thus cause all kinds of problems. Unfortunately many of them are still little known and measuring them for a diagnosis would be undeniably difficult. Still further theoretical research may provide some clues in the future. (
Title: Re: FAAH Inhibitors
Post by: mxh on March 17, 2022, 12:33:19 PM
Not giving an explanation of the supposedly super-important thing you're talking about (or making it incredibly hard to glean from anything) is one of the impossible, unbelievable bad habits on the internet that for no imaginable reason are usually tolerated. One would imagine having an instinct to the contrary would be the most straightforward thing (or even making some remarks on the lack of explanation).
Note: this especially regards the huge first post, but also that explanations might be scattered (and excessive use of abbreviations to start with etc).
Title: Re: FAAH Inhibitors
Post by: Progecitor on March 17, 2022, 01:53:30 PM
Not giving an explanation of the supposedly super-important thing you're talking about (or making it incredibly hard to glean from anything) is one of the impossible, unbelievable bad habits on the internet that for no imaginable reason are usually tolerated. One would imagine having an instinct to the contrary would be the most straightforward thing (or even making some remarks on the lack of explanation).
Note: this especially regards the huge first post, but also that explanations might be scattered (and excessive use of abbreviations to start with etc).

I have already mostly disproved this theory for myself. I thought the research thread was about trying to create new theories then either proving or disproving them. In this case my fault lies in my enthusiasm about saffron and maca. Both are known to have a FAAH inhibitory property and both ameliorate my symptoms really well and cause anti-depression. It is thought that the anti-depressive effect of saffron is due to FAAH inhibition. So the fault is not only mine, as researchers also made a mistake by stating so. This is also not a highlighted thread, so it is considered less important. Maybe you should check out the others instead. I was also considering to delete this thread earlier, but I thought some valuable information could be still found here, especially as there were a few POISer who reacted really well to CBD oil.
Theories are abound on the forum. For example testosterone boosters are also beneficial in my case, however a lack of testosterone also can’t explain everything, like my success with several estrogenic supplements.
Official research is also not without fault, just consider how Dr Waldinger gave up on the idea of POIS being a simple allergic reaction. Of course we could all wait for official research to get on, but that progresses at snails pace and I feel like my time is running out to make any real change about my life.
You are right in that I am riddled by bad traits and habits, but most of us write these posts with bloodshot eyes while also suffering from brain fog and a number of other ails. The “research” I am doing is more like a therapy for myself to give me some hope that I lost in the previous decades. 
However if it bothers you so much and any other POISer also thinks so then I will delete this thread.
Title: Re: FAAH Inhibitors
Post by: berlin1984 on March 17, 2022, 03:46:52 PM
Please don't delete anything.
You can edit the first post and add a "EDIT: bold red warning" or something like that.

(but still it is valuable if certain supplements help you, they might help others too)
Title: Re: FAAH Inhibitors
Post by: Progecitor on March 17, 2022, 04:40:05 PM
Thanks for the suggestion! I did as you advised.