Author Topic: FAAH Inhibitors  (Read 15471 times)


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Re: FAAH Inhibitors
« Reply #40 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #41 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.


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Re: FAAH Inhibitors
« Reply #42 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #43 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #44 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #45 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)


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Re: FAAH Inhibitors
« Reply #46 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #47 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #48 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #49 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).
« Last Edit: March 17, 2022, 12:48:06 PM by mxh »


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Re: FAAH Inhibitors
« Reply #50 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.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.


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Re: FAAH Inhibitors
« Reply #51 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)


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Re: FAAH Inhibitors
« Reply #52 on: March 17, 2022, 04:40:05 PM »
Thanks for the suggestion! I did as you advised.
The cause is probably the senescence of sexual organs and resultant inducible SASP, which also acts as a kind of non-diabetic metabolic syndrome.