Author Topic: FAAH Inhibitors  (Read 5744 times)

Progecitor

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Re: FAAH Inhibitors
« Reply #20 on: May 02, 2021, 05:35:17 AM »
Hello Progecitor, did you see that I sent you a personal message?

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

I checked into it a bit, but the involvement of GABA seems controversial so far. You could be right, but I don't have any hormonal measurements and I haven't tried many GABAergic compounds either. I plan to have some hormonal tests done later this year and maybe some genetic tests next year, but the pandemic and my earnings don't make this easy. I highlighted some definitions as I am also just learning about these things and it makes this a bit easier to understand.
What I found so far:
3a-diol is a positive allosteric modulator of the GABA(A) receptor which means that it changes the receptor's response to stimulus. Positive modulators increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both.[/i]
https://en.wikipedia.org/wiki/3%CE%B1-Androstanediol
https://en.wikipedia.org/wiki/Allosteric_modulator

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

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

Lemon balm (Melissa officinalis) is a GABA transaminase inhibitor. Inhibition of GABA transaminase enzymes reduces the degradation of GABA, leading to increased neuronal GABA concentrations.
https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid

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

The most potent and selective inhibitors of 5a-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea. Riboflavin was also identified as a 5a-reductase inhibitor.[/b]
https://en.wikipedia.org/wiki/5%CE%B1-Reductase
It is a fairly reasonable suspicion that linolenic acid enhances my POIS. I have other problems with zinc that may be not directly related to POIS. I had some reaction to green tea, but I don't exactly remember what and I have to retest it before I can say any more. Riboflavin is also known as vitamin B2, but I haven't tested that separately, so I am not sure.

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

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

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

An elevated bilirubin level also seems to be a risk factor in COVID-19 infection, even though the infection wasn't very serious for me. Based on research bilirubin actually protects the virus against the antibodies.
https://advances.sciencemag.org/content/early/2021/04/22/sciadv.abg7607

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

https://www.jneurosci.org/content/35/27/10039.short
Constitutively active receptor: A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist.

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

https://onlinelibrary.wiley.com/doi/full/10.1111/ics.12559

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

https://blog.metagenics.com/post/2019/10/17/get-to-know-pea-and-its-history/
I took a soy lecithin supplement a few years ago and I think it helped a little at the time, so I will need to test it again.

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

https://sci-hub.se/https://www.karger.com/Article/Abstract/500168

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

https://www.frontiersin.org/articles/10.3389/fphar.2018.00998/full

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

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

Table 1. contains a list of Functional Foods rich in micronutrients that activate PPARA and PPARG and induce pharmacological effects!
https://www.sciencedirect.com/science/article/pii/S2352289520300126

I think PPARA agonists may help me, so I will have to thoroughly test them. A short list of PPARA agonists: PEA (soy lecithin, egg yolk, and peanut meal) niacinamide, oleic acid (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).

Prospero

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Re: FAAH Inhibitors
« Reply #21 on: May 02, 2021, 05:43:32 AM »
To be precise, as I wrote you, it's not *my* argument, but someone else wrote this to me (as an hypothesis) and it made me think about what you were researching. I don't know if there is such a connection, it exceeds greatly my own competence.
Whatever, thank you for your findings on this topic.
« Last Edit: May 02, 2021, 06:12:47 AM by Prospero »

Progecitor

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Re: FAAH Inhibitors
« Reply #22 on: May 02, 2021, 11:50:51 AM »
To be precise, as I wrote you, it's not *my* argument, but someone else wrote this to me (as an hypothesis) and it made me think about what you were researching. I don't know if there is such a connection, it exceeds greatly my own competence.
Whatever, thank you for your findings on this topic.

The message I wanted to convey is that the theory is definitely valid as even official researchers proposed it. However as of this moment I can't clearly prove or refute it based on my personal experience and that is why I highlighted possible ways to modulate the process and check it against reality. Refuting it for one case doesn't necessarily mean that it is not true for at least some POIS cases.  At least PPARA agonists seem highly worthy to trial as many of them worked for one or another POISer. If someone has about the same experience with all of them then it is an indirect evidence for PPARA involvement in their personal POIS case be it either up- or down-regulation.

Prospero

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Re: FAAH Inhibitors
« Reply #23 on: May 02, 2021, 05:28:30 PM »
Yes, I understand very well, I just wanted to make this clarification because, considering my absence of skills, members of the forum may be surprised by the assertive tone of the quote, which is not from me.
As for the specific link with bilirubin, I have still some difficulty to clarify the relation between low glucuronidation (of 3adiol) and 5a-reductase inhibition.
I also noticed that I had rather bad reactions to zinc and green tea (worsening of some of my usual Pois symptoms, notably tachycardia) but it may have nothing to do with 5a-reductase.
Lemon balm seems beneficient for me too, for my nervous symptoms. As for GABA as a supplement, some people seem to think that it can be transformed into glutamate and is not necessarily useful as a GABA receptor agonist.

Progecitor

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Re: FAAH Inhibitors
« Reply #24 on: May 04, 2021, 03:44:24 PM »
The combination of lungwort tea and saffron is quite extraordinary. Unfortunately even this can't completely overcome POIS, but this is the best thing I have found so far. It reduces all aspects of POIS considerably. It is definitely a profound painkiller. It feels like most of my pain receptors are blocked. I can only imagine that a very high anandamide level desensitizes TRPV1 receptors. I can hardly feel the thighs and my dick feels like a limp mass. Well it probably shouldn't be used if someone actually wants to do sex, but it is a superb after-event treatment nonetheless. If any POISer doesn't have any positive reaction to this I can't imagine their case has anything to do with the endocannabinoid system or with FAAH inhibitors at least.

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

Pulmonariae officinalis (Lungwort) (Apparantely there are multiple lungworts, so NOT Lobaria pulmonaria)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910643/
The P. officinalis extracts showed slightly lower acetylcholinesterase inhibitory effects – 87.7%, tyrosinase inhibitory effects – 73.69%,

Saffron
https://pubs.acs.org/doi/10.1021/jf300589c
Saffron extract showed moderate AChE inhibitory activity (up to 30%),

I wonder about the chest pain you describe. I never have chest pain. Maybe the tea fixed something there for you if it claims it's for chest infections.
https://www.planetayurveda.com/library/lungwort-pulmonaria-officinalis/
https://www.healthbenefitstimes.com/lungwort/ Also claims it's for urinary tract infections

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

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

I haven't read everything about lungwort (Pulmonaria officinalis), but it is good to know that it also contains Pyrrolizidine alkaloids (PA). However this is a bit worrying finding.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910643/
Pyrrolizidine alkaloids are produced by plants as a defense mechanism against insect herbivores.
Unsaturated pyrrolizidine alkaloids are hepatotoxic, that is, damaging to the liver. PAs also cause hepatic veno-occlusive disease and liver cancer. PAs are tumorigenic. Disease associated with consumption of PAs is known as pyrrolizidine alkaloidosis.

https://en.wikipedia.org/wiki/Pyrrolizidine_alkaloid
So even though it is filled with a lot of anti-cancerous compounds its excessive use could be detrimental in the long run. I still think it is a good choice for days when I want to have an O, but it doesn't seem like a good idea to use it on a daily basis.
Common centaury (Centarium umbellatum) is also available here, so I will surely try and see how it works.
Tussilago farfara, commonly known as coltsfoot is also used to treat asthmatic and flu symptoms, so I thought it would be interesting to see what it does. Unfortunately coltsfoot contains the most toxic and carcinogenic pyrrolizidine alkaloids, so it is definitely not for someone with a Gilbert's disease. Although experts have bred a variety that practically contains no detectable pyrrolizidine alkaloids.
Tussilago farfara leaves have been used in traditional Austrian medicine internally (as tea or syrup) or externally (directly applied) for treatment of disorders of the respiratory tract, skin, locomotor system, viral infections, flu, colds, fever, rheumatism and gout.
Tussilago farfara contains tumorigenic pyrrolizidine alkaloids. Senecionine and senkirkine, present in coltsfoot, have the highest mutagenetic activity of any pyrrolozidine alkaloid. In response, the German government banned the sale of coltsfoot. Clonal plants of coltsfoot free of pyrrolizidine alkaloids were then developed in Austria and Germany. This has resulted in the development of the registered variety Tussilago farfara 'Wien', which has no detectable levels of these alkaloids.

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

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

A longer list of PPARA agonists (they can be found in this thread): fluoxetine, mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, cardamom (limonene and kaempferol), Tribu Saponin from Tribulus terrestris, AEA, OEA, and PEA, rosmarinic acid and biochanin A, PEA (soy lecithin, egg yolk, and peanut meal), niacinamide, oleic acid - OEA (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).
Of course I will try to find more and test as many as I can to see if there is a real connection.

Progecitor

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Re: FAAH Inhibitors
« Reply #25 on: May 11, 2021, 02:45:05 PM »
I think acetylcholinesterase and tyrosinase inhibition may not lie at the core of my problems, but currently I also can't definitely rule it out. I tested common centaury (Centarium umbellatum), but it had no major effect on my POIS. It is true that it has a positive effect on POIS, but it is very weak compared to lungwort. To tell you the truth I couldn't drink more than 4 deciliter of its tea, as it has such a bitter and sour taste that its practically impossible to consume a greater amount. Nevertheless even a cup of lungwort tea has a very noticeable effect, so it is unlikely that the same mechanism is involved. In the previously mentioned study they used ethanolic extracts, but I am not sure if it could make such a big difference.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910643/

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

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

https://www.researchgate.net/profile/Xin-Cao-11/publication/337748759_Progress_in_Target_Drug_Molecules_for_Alzheimer%27s_Disease/links/5ef1dc7192851ce9e7fce0f0/Progress-in-Target-Drug-Molecules-for-Alzheimers-Disease.pdf

Echinacea is a FAAH inhibitor!
Fatty acid amide hydrolase inhibition ranged from 34–80% among E. angustifolia genotypes and from 33–87% among E. purpurea genotypes. Simple linear regression revealed the caffeic acid derivatives caftaric acid and cichoric acid, and the alkylamide dodeca-2E,4Z-diene-8,10-diynioc acid 2-methylbutylamide, as the strongest determinants of inhibition in E. purpurea (r*=0.53, 0.45, and 0.20, respectively) while in E. angustifolia, only CADs were significantly associated with activity, most notably echinacoside (r*=0.26). Regression analysis using compound groups generated by hierarchical clustering similarly indicated that caffeic acid derivatives contributed more than alkylamides to in vitro activity. The results suggest that several phytochemicals may contribute to Echinacea's cannabimimetic activity and that ample variation in genotypes exists for selection of high-activity germplasm in breeding programs.
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1289-9569

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

https://www.sciencedirect.com/science/article/pii/S1567576909001015

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

https://en.wikipedia.org/wiki/Goldenseal

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

https://sci-hub.se/https://www.karger.com/Article/Abstract/435934

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

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0704220

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538700/

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

https://www.mdpi.com/2304-8158/10/1/29/htm

I took soy lecithin [1200 mg softgel] again and it seems to have a beneficial effect, although it is relatively weak. If I take two with only a few hours difference it may cause a weak cramping heartache as a side-effect.
Artichoke tea works relatively well. Drinking 1 liter seems to have a weak to moderate efficacy. It has no rapid action, only long term (6-12 hours) benefit.
Also alfalfa works like a charm, but more about this in my next post.
« Last Edit: May 11, 2021, 02:54:57 PM by Progecitor »

berlin1984

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Re: FAAH Inhibitors
« Reply #26 on: May 12, 2021, 12:27:48 PM »
I have to say that Saffron (Affron©)  is the single best supplement I discovered in the last year. (thanks!)

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

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

It's not perfect yet though.

Maybe I should try to combine it with Ashwagandha again which I stopped because after some weeks it leads to heart palpitations. Hm.
By the way, Ashwagandha extract inhibits acetylcholinesterase.

Progecitor

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Re: FAAH Inhibitors
« Reply #27 on: May 15, 2021, 05:32:18 AM »
Lucerne which is also known as alfalfa surely works! The product I bought is called lucerne [500 mg per pill] containing powdered lucerne made with cold pressurized method without any additives. For the first time I took it I tested it right away against an O and amazingly it completely prevented POIS! I had practically no symptoms. No bloodshot eyes, no coldness, no fatigue or brain fog. On the next morning I couldn't feel any enlarged lymph nodes in the breasts and I had no muscle fatigue, although I wouldn't say it was full of energy. The stool was a bit harder than usual, but it was completely normal with no burning feeling at all. I had a really slight headache in the morning, but it passed on its own after a few hours. To be frank I think I used quite a high dose as the daily recommendation is 5 pills (2.5 g) and I took 8 pills (4.0 g or 4000 mg) on that day. I took three pills in the morning then about 8-10 hours later took another two. Two hours later I had an O and shortly after took another two. Before going to sleep I had another one. Lucerne doesn't seem to have a rapid effect onset, so it must have been important that I also took it in the morning. Of course I don't believe that it will keep working this well as the effectiveness of saffron and MACA also reduced after a short time, but it is still a very good product against my POIS.
Actually I realized that most of the stuff that work have a slow effect onset. They can ameliorate POIS if it occurs, but I think it is much better to also take them well beforehand as it is better to reduce POIS when it happens, so it won't upset the homeostasis to a greater extent. I haven't exactly figured out the exact values for most of the stuff and it may be difficult as well, but for most it is in the 6-12 hours range after their consumption. I think Echinacea works best if taken about 6 hours before an O, while alfalfa may be best taken about 10 hours beforehand. Many here claim that niacin or niacinamide works best when the flare response happens, but I don't think this can be applied to my case. I think I need to take it several hours before O to have the best effect. Of course I haven't confirmed this yet, but I will definitely need to. This may also mean that when combining different components their synergy may be more ideal if they are not taken at once, but also considering their peak efficacy.
Now the problem is that I don't know why lucerne/alfalfa worked so well. Earlier I proposed that alfalfa could be a potent FAAH inhibitor due to its daidzein content. What I can gather is that daidzein can be found in the root and the sprout, but I am not sure how much if any can be found in the plant itself. I also had problems with kudzu root which contains daidzein. Kudzu also contains puerarin which is probably (by a quick scholar check) an agonist of all PPARs (PPARpan), but I am not sure if it could be the reason why it didn't work. As a third possibility I wondered if another compound could be the reason. As alfalfa is high in phytoestrogens this seemed to be an interesting prospect. Searching about coumestrol something rather surprising and interesting information turned up. Coumestrol is actually a potent inhibitor of the AKR1C family which includes different hydroxysteroid dehydrogenases that are involved in the conversion of hormones with different affinities.
It turns out that many of the flavanoids previously mentioned have an inhibitory effect on these enzymes. This gives a brand new perspective to be explored, but it may not be easy to reach a definite conclusion without actual measurements.

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

https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Developmental+effects+of+dietary+phytoestrogens+in+Sprague-Dawley+rats&btnG=

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

https://en.wikipedia.org/wiki/Alfalfa

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568198/

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

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

Check out Table 1!
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0303720706003807

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939640/

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

Also check out the Tables!
https://sci-hub.se/https://link.springer.com/chapter/10.1007/978-1-4757-5235-9_14

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

https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0303720700004226

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

https://en.wikipedia.org/wiki/Gynecomastia

The overexpression of aromatase leads to high estrogen levels, so aromatase underexpression should be considered as well.
https://en.wikipedia.org/wiki/Aromatase_excess_syndrome

In normal individuals, a painful/stressful stimulus up-regulates Substance P in the nociceptive relay neurons and serotonin levels drop, consistent with a loss of feeling of well-being. Substance P has been found to stimulate aromatase, which would catalyze the conversion of testosterone to estradiol within the CNS, with subsequent upregulation of opiates and consequent dampening of pain. In fibromyalgia patients, deficient levels of testosterone are predicted to result in a "frustrated" cycle (due to lack of substrate) in which conversion of testosterone to estradiol is inadequate for induction of opiate-mediated dampening of nociceptive signals, resulting in abnormal chronic, diffuse, widespread pain. Estradiol, refers to 17-beta estradiol.
https://www.sciencedirect.com/science/article/pii/S1567576915002490

However, in the presence of acerola cherry extract, both soy and alfalfa extracts potently inhibited the formation of low-density lipoprotein (LDL). These findings show that acerola cherry extract can enhance the antioxidant activity of soy and alfalfa extracts in a variety of LDL oxidation systems. The protective effect of these extracts is attributed to the presence of flavonoids in soy and alfalfa extracts and ascorbic acid in acerola cherry extract, which may act synergistically as antioxidants. It is postulated that this synergistic interaction among phytoestrogens, flavonoids, and ascorbic acid is due to the "peroxidolitic" action of ascorbic acid, which facilitates the copper-dependent decomposition of LDL peroxides to nonradical products; this synergy is complemented by a mechanism in which phytoestrogens stabilize the LDL structure and suppress the propagation of radical chain reactions.
The combination of these extracts markedly lowers the concentrations of phytoestrogens required to achieve significant antioxidant activity toward LDL.

https://pubs.acs.org/doi/abs/10.1021/jf0007028

berlin1984

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Re: FAAH Inhibitors
« Reply #28 on: May 15, 2021, 02:10:54 PM »
You are writing a lot of text and even the bold-ing does not help to process it.

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

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

That said, I actually have alfalfa extract here because when I was following the testosterone deficit theory I wanted to have it boost my testosterone..
If you search the forum, it comes up a bit.
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)

berlin1984

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Re: FAAH Inhibitors
« Reply #29 on: May 18, 2021, 07:07:15 AM »

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.

Progecitor

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Re: FAAH Inhibitors
« Reply #38 on: June 15, 2021, 02:02:36 PM »
Testosterone suppresses PPARG activity, while estrogen behaves oppositely if applied in small (up-regulates PPARG) or high doses (down-regulates PPARG). PPARG shares co-activators with both ER and AR and they compete for co-activator binding.

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

https://sci-hub.se/https://www.sciencedirect.com/science/article/pii/S1382668916302101

Progecitor

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Re: FAAH Inhibitors
« Reply #39 on: June 21, 2021, 12:50:17 PM »
I may have neglected to emphasize that my POIS reacts to a lot of diet elements and in my opinion it is a rather convincing evidence of the involvement of PPARs. For many POISers the effective medications, besides their other effects, are known PPAR ligands and to me it seems almost undeniable that PPARs play a central role in our disease even if the same treatment may not work for everyone.

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

https://sci-hub.se/https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.2782

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