Author Topic: FAAH Inhibitors  (Read 1106 times)

Progecitor

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Re: FAAH Inhibitors
« Reply #30 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.
https://poiscenter.com/forums/index.php?topic=2032.msg15981#msg15981 <- 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.
https://www.frontiersin.org/articles/10.3389/fnbeh.2018.00249/full
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.
https://www.oatext.com/pdf/JTS-5-283.pdf
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?

berlin1984

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Re: FAAH Inhibitors
« Reply #31 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.

Progecitor

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Re: FAAH Inhibitors
« Reply #32 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.

https://www.frontiersin.org/articles/10.3389/fnbeh.2018.00249/full

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.

https://link.springer.com/content/pdf/10.1007/s00709-020-01488-y.pdf

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.
https://www.sciencedirect.com/science/article/abs/pii/S088915912032482X

Progecitor

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Re: FAAH Inhibitors
« Reply #33 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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516960/

This may put Indomethacin in a whole new light.
Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2.
https://pubs.acs.org/doi/abs/10.1021/jm3017656

berlin1984

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Re: FAAH Inhibitors
« Reply #34 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

Disaster

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Re: FAAH Inhibitors
« Reply #35 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..
POIS sufferer for over 3 decades. Has progressively gotten worse over the years and I became completely disabled around 2011. My case of POIS is very severe.

Progecitor

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Re: FAAH Inhibitors
« Reply #36 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773459/

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.
https://en.wikipedia.org/wiki/Beta-Sitosterol

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
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=%27Testosterone+Boosting%27Supplements+Composition+and+Claims+Are+not+Supported+by+the+Academic+Literature&btnG=

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.

https://pubs.rsc.org/en/content/articlelanding/2019/fo/c9fo00862d/unauth#!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.

http://actamedicamarisiensis.ro/wp-content/uploads/2015/09/2012-5-5x.pdf

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.

https://www.mdpi.com/2079-7737/10/4/287/htm

Progecitor

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Re: FAAH Inhibitors
« Reply #37 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.