POIS treatment: theory & supplement stack

[nanna1]

  After over a decade, I believe I have cured my POIS. I wanted to open source my supplement stack to get feedback/improvemnets and to help others going through what I went through.

  During orgasm there is a transient increase in norepinephrine release [1] (see Neuroendocrine responses to arousal and orgasm).

  Postorgasmic illness syndrome (POIS) occurs when there is an overexpression of the α1-adrenergic (a1A) receptor and a subsequent over-stimulation of a1A by rising norepinephrine levels [2]. Part of the effect of α1-adrenergic , a1A, stimulation is to obtain methyl groups (choline) from the phospholipid bilayer stored in the form of phosphatidylcholine (PC) [3]. a1A stimulation upregulates the enzymes Phospholipase A2 and C, which remove a PC-arachidonic acid molecule from the cell wall (lipid bilayer) and separates PC from arachidonic acid (omega-6 fatty acid, AA) [4]. PC is now free to produce choline and replenish the pool of methyl groups consumed in both semen and neurotransmitter production.

  However, the release of arachidonic acid, or AA, is problematic since it is a key substrate for the production of inflammatory hormones by the enzymes 5-LOX, COX-2 and the CYP450 group [4]. It is the rapid release of AA and mass production of inflammatory hormones (such as prostaglandin E2) that triggers sickness associated with POIS.

  During normal sexual activity, histamine is not elevated (Becker et. al. 2011). However, POIS-like symptoms could be stimulated by non-coital external allergens (food, pollution, etc...), by replacing norepinephrine with either histamine or glutamate, and replacing a1A receptor with either the h1-histaminergic (h1H) or NMDA (NR2B) receptor. For example, histamine stimulation of h1H upregulates the enzyme Phospholipase A₂, leading to the same release of PC and AA as discussed above [5, 6].

  Blocking both of the processes represented by red arrows in the figure above would, according to this theory, stop POIS. In other words, each red path is a required step for the disease to manifest. And the upregulation of NF-kB (NF-kappa Beta) by reactive oxygen species (ROS) is a required step for the increased production of COX-2 and inflammation.
  We can refer to the cascade of events, starting with simulation of the a1A, h1H, NR2B receptors and ending with the production of inflammatory prostaglandins, as the POIS Cascade. To stop POIS, you have to modify the POIS Cascade by inhibiting three key events:
1.   α1-adrenergic and h1-histamine receptor overexpression
2.   NF-kB upregulation and inflammatory cytokine production
3.   arachidonic acid production and release from the PC-arachidonic acid complex

  (1) a1A receptor expression is down regulated by the universal methyl group donor S-adenosyl-methionine (SAM-e) by donating its methyl group through methyltransferase enzymes [7]. In this way, SAM-e prevents the breakdown of the phospholipid bilayer [8] and the subsequent metabolism of AA [9]. h1H receptor expression is down regulated by Protein Kinase C (PKC) inhibition [10]. PKC is potently inhibited by thiamine diphosphate, the active form of vitamin B1 [11]. Moreover, thiamine supplementation reduces median histamine levels [12].
  (2) Vitamin D3 is a strong inhibitor of NF-kB and COX-2 production [Ref link]. D3 accomplishes this by inhibiting the production of inflammatory cytokines such as TNF-a, IL-1B, IL-6, etc... [schematic diagram]
  (3) In the absence of dietary AA, omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce AA incorporation into the phospholipid bilayer and decrease the production of inflammatory prostaglandins such as PGE₂ [4, 13]. Moreover, EPA directly competes with AA for access to enzymes 5-LOX and COX-2 [4]. And unlike AA, the metabolic products of EPA interaction with these enzymes are anti-inflammatory (link).

For a literature review of POIS related research see POIS literature review:

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  Below I provide two separate supplement stacks that have given me complete relief of POIS symptoms. "The Betaherpesvirinae stack" is a prepack that targets a specific reactivation mechanism of cytomegalovirus (CMV, HHV-5) and herpes virus 6 (HHV-6) involving suppression of NF-kB and COX activity (see RefSE1, RefSE2). More details on how herpes viruses may initiate POIS can be found here (link). "The POIS Cascade stack" is the general daily health supplement (and vegan diet) regime that I use to treat my POIS, NE, and reduce exercise induced DOMS. These are two separate stacks which are not meant to be taken together. The below quantities for each stack are listed per dose.

The POIS Cascade stack:
On an empty stomach with water or juice, twice daily (water soluble):
---SAM-e (enteric coated)(200mg) [terminal methyl donor, a1A downregulator]
---Pyridoxal-5-phosphate, P-5-P vitamin B6 (2mg - 25mg) [homocysteine regulator]
---Metafolin or folinic acid, vitamin B9 (less than 200mcg) [methyl group cycler]
---cyanocobalamin, vitamin B12 (>50mcg, sublingual) [methyl group cycler]
---Pick from one of the following three methyl group donors:
    1. tri-methylglycine, betaine (1.5g) [methyl group donor]
    2. alpha-glycerophosphocholine, alpha-GPC (600mg) [methyl group donor]
    3. liposomal vitamin C (2g) (also containing phosphatidylcholine) (source1, source2, source3)
With food, twice daily (fat soluble):
---Benfotiamine, vitamin B1 (150mg) [h1H downregulator]
---conjugated linoleic acid, CLA (2g) [NF-kB inhibitor and COX-2 downregulator]
---eicosapentaenoic acid, EPA (900mg) [AA synthesis inhibitor, AA blocker]
---docosahexaenoic acid, DHA (150mg) [AA synthesis inhibitor]
---vitamin D3 (1000 IU) [NF-kB inhibitor and COX-2/IDO/TDO down-regulator]

Betaherpesvirinae stack:
Taken 2 hours prior to sexual activity (prepack):
Vasoconstrictors (my modified version of Excedrin):
---Paracetamol 500mg
---indomethacin 50mg
---caffeine 130mg (from Matcha green tea, one brewed cup, whole powder)
Immune regulators:
---vitamin D3 (2000IU sublingual)
---citrulline malate (6g)
---liposomal vitamin C (2g) (also containing phosphatidylcholine) (source1, source2, source3)
Drug detox antioxidants:
---N-acetylcysteine (1.2g)
---selenomethionine (200 micrograms)

Note: Many of these supplements have slow diffusion across the blood/brain barrier and/or slow incorporation into the phospholipid bilayer. So it may take 3 to 4 weeks of consistent supplementation before you are able to assess the full benefit. I continue daily maintenance of supplementation with the POIS Cascade Stack even after seeing my symptoms disapear.
   About SAM-e: SAM-e plays a unique role in the Homocysteine Cycle (see #1) and cannot be replaced by any other methyl donor or cycler. SAM-e may upset your stomach the first time you take it; this is normal. Do not take SAM-e within 5 hours of your typical bedtime or you may experience trouble going to sleep.

   About Methyl donors: For the alpha-GPC option, start out taking apha-GPC once daily at 300mg and work your way up to a twice daily dose at 600mg over the course of one week. Large doses of alpha-GPC without being acclimated first could cause choline-induced lower-back and upper-leg pain. The advantage of taking methyl donors such as choline and betaine (TMG) is that they offer a folate-independent path to reducing homocysteine and recycling SAM-e (see #2 in Homocysteine Cycle). I believe this folate-independent and (MTHFR)-independent SAM-e production by choline/betaine was critical for eliminating my POIS symptoms. Di-methyglycine (DMG) does not offer this advantage, and could make problems worse for those who are undermethylated/folate-deficient.

   About vitamin B6: The amount of vitamin B6 here (2mg) is roughly 100% of the US recommended daily allowance (RDA). My daily B6 consumption does not exceed 25mg as an upper limit. However, typical branded B6 and B complex supplements may exceed 200mg (10,000%) and are toxic when taken daily.
   About folate B9: (200 microgram) is a safe daily dose. For folate-cancer data, please see Table 1: cancer endpoints under the Outcomes heading.
   About vitamin B12: B12 has an extremely low toxicity. Between 50 to 1000 mcg can be taken per day.

   About Omega-3: Because of the way that EPA is metabolized in the body, it does not have any toxicity in the body. So, the more the merrier! DHA has a theoretical toxicity, but this has never been demonstrated in vivo. Omega-3s compete with and are a substitute for omega-6s like AA. Therefore, it may be just as important to reduce dietary omega-6 (AA) consumption. I have almost eliminated certain fatty-meats (i.e. pork and beef) from my diet since this is the largest source of arachidonic acid in North America.

  About Vasoconstrictors: The vasocontrictors (Paracetamol 500mg, indomethacin 50mg, caffeine 130mg) can be replaced by Excedrin (acetaminophen 500mg, aspirin 500mg, caffeine 130mg). Paracetamol, which is another name for acetaminophen or Tylenol, is a Endocannabinoid Enhancer. The three drugs work in synergy to downregulate COX-1 and COX-2 activity. The respective roles of each should be considered when substituting or removing the ingredients. The research indicates that selenomethionine detoxifies indomethacin (Ref1, Ref2, Ref3, Ref4) and N-acetylcyteine detoxifies acetaminophen/Tylenol (Ref4, Ref5, Ref6). In adddition to inhibiting NF-kB, selenomethione and N-acetylcyteine boost glutathoine and should be taken to minimized potential side-effects of Excedrin/Betaherpesvirinae stacks. The below figure shows the dose timing for the vasoconstrictors. t_start is when the dosing starts. t_max is when sexual activity can begin. t_1/2 is the window of time when the vasocostrictor is effective (half-life). This effective window for the Betaherpesvirinae stack is about 3 hours.


Final note:
  I avoid concentrated extracts of curcumin, luteolin, quercetin, ginger, and peppermint because from my experience, these flavonoids reduced the quality and quantity of my semen. I noticed this effect in my semen when I used to take concentrated extracts of curcumin and luteolin. I discovered this by accident about a year and a half ago after taking large doses of curcumin and luteolin. I noticed a slight thinning of my semen and reduced volume. When I stopped taking curcumin and luteolin (daily), after about a week my semen recovered. Thinking that this was a coincidence, I resumed only curcumin (daily), but after a few days I noticed the same effects on reduced volume.
  These were not rigorous test, but after some research, I found that flavonoids mimic steroids in the body for their effects. In other words, flavonoids derive their beneficial effects primarily through steroid signaling [15] (anti-inflammatory[16], anti-oxidant [17], mast cell stabilizing [18], IDO/TDO inhibiting [19], neuroprotection [20], cAMP-PDE inhibitor [21]). The US Environmental Protection Agency list quercetin as one of the strongest estrogens found in the environment [22]. However, it is important to point out that whole-herbs like licorice (contains quercetin) and tumeric do not appear to have this negative effect, and I have not experienced any negative side effects on sperm when taking whole-herbs. My concern about using flavonoid extracts is purely out of concern for the health of my reproductive system, and is not related to reducing POIS symptoms. Like steroids, it appears that flavonoids can also potently reduce inflammation and other POIS symptoms. I do make it a point to get natural levels of flavonoids through diet (capers, onions, apples, broccoli, spicy foods, tumeric-based vegetable currys). However, I personally do not take active hormones.
  For sperm consistent herbal supplements, I sometimes like taking lycopene, lutein, zeaxanthin, and oils like olive oil, ahiflower oil and/or cinnamon oil. Each of these oils has a unique protocol for supplementation to receive the maximum benefit. Please do the research before you buy.

References:
1.   Specificity of the neuroendocrine response to orgasm during sexual arousal in men. (2003)
2.   Norepinephrine stimulates arachidonic acid release from vascular smooth muscle via activation of cPLA2. (1998)
3.   Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism. (2013)
4.   Dietary long-chain n−3 fatty acids for the prevention of cancer: a review of potential mechanisms. (2004)
5.   Histamine-induced release of arachidonic acid and of prostaglandins in the peripheral vascular bed: mode of action. (1980)
6.   Histamine-induced inositol phospholipid breakdown mirrors H1-receptor density in brain. (1983)
7.   Effects of the novel antidepressant S-adenosyl-methionine on alpha 1- and beta-adrenoceptors in rat brain. (1989)
8.   S-adenosyl-l-methionine inhibits phosphoinositide metabolism in the rat brain synaptosomal suspensions. (1993)
9.   Anti-inflammatory activity of S-adenosyl-L-methionine: Interference with the eicosanoid system. (1983)
10.   Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-δ/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells. (2013)
11.   Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. (2003)
12.   Effects of thiamine administration on hypothermia and hypothalamic histamine levels in dietary-induced thiamine deficient rats. (1990)
13.   The influence of fish oil diet and norepinephrine treatment on fatty acid composition of rat heart phospholipids and the positional fatty acid distribution in phosphatidylethanolamine. (1986)
14.   Inclusion of thiamine diphosphate and S-adenosylmethionine at their chemically active sites.
15.   Estrogen and progestin bioactivity of foods, herbs, and spices. (1998) also link to full article
16.   Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury.
17.   Antioxidant status and reproductive hormones in women during reproductive, perimenopausal and postmenopausal phase of life. (2014)
18.   Progesterone Inhibits Mast Cell Secretion (2006)
19.   Tryptophan metabolism, disposition and utilization in pregnancy (2015)
20.   Flavonoids Induce the Synthesis and Secretion of Neurotrophic Factors in Cultured Rat Astrocytes: A Signaling Response Mediated by Estrogen Receptor (2013)
21.   Progesterone and estradiol concentrations in nonpregnant and pregnant human myometrium. Effect of progesterone and estradiol on cyclic adenosine monophosphate-phosphodiesterase activity.
22.   Endocrine Disruptor Screening Program (EDSP) Estrogen Receptor Bioactivity

[devastated]

Very interesting post. Can someone with sufficient medical knowledge verify this?

[paradoxx]

Hi nanna1, thanks for your research and welcome to the forum. What are the symptoms you had during your POIS cycles before you found this cure? Did all your symptoms stop within 1 month of taking the described stack?

[nanna1]

Hi paradoxx,
My symptoms were persistent headaches, sneezing, runny nose, fatigue, pain in my left ear, memory/concentration problems and lacking motivation. This lasted 5 to 8 days. Fortunate my job has flexible hours, because some days I couldn't go to work during the normal hours because I was out of it. My social life was in the dumps. I had tried everything herbal supplement, fasting (from food), exercise.

I had been taking B6, B9, B12 vitamins, fish oil, alpha-GPC and Aspirin with some success over several months. Very significant improvements but not cured. One day I added SAM-e and vitamin B1. Within 24, all symptoms when away. Then the next day the symptoms came back so I kept taking them and after some research added vitamin D3 and stopped taking Aspirin. I feel great now! No symptoms. Getting ready to go play some basketball with friends. These are all supplements that I found on other peoples POIS post that worked for them. Once I found out what worked for me I did the research to find out why. The only downside to the "cure" is I have to keep taking the supplements or else after a week or so the symptoms will come back.

[Quantum]

Hi nanna1,

Thanks for sharing your information.  I am glad you have found empirical success in controlling your symptoms

It is not always possible to explain why what we take is effective, but I see you have taken the time to build a complete hypothesis about POIS pathophysiology.  That's quite rare, usually people are not at ease enough with scientific articles and medical terminology to do so  ( out of curiosity, are you working in a scientific field ?).  Thanks for this great implication from your part, I know the kind of time investment needed to do this.

Some of the metabolic pathways you refer to has already been discussed and presented by forum members.  For example, the methyl pathway and methylation problems have been discussed a lot by Kurtosis, a few years ago.   The inflammatory cytokines production and AA pathways have been presented by myself, among others.   However, your inclusion of the alpha-2 receptors is rather new.  What led you to believe that the alpha1-adrenergic receptors are highly implicated in POIS ? I ask because strong stimulation of alpha1 receptors should cause high blood pressure.  This manifests in some POIS sufferers, but not every one.  And, in others, it is rather the opposite, it is hypotension that manifests  ( and rather severe low blood pressure, in my case, when left untreated ).  At any rate, like you may have read on the forum, I really think there is more than one type of POIS, with some different manifestations, but sharing a common pattern, so it is possible that one of these types implies the a1 receptors, but not the other types.

Your hypothesis is clearly on the neurologic side, with no mention of a possible prostate antigen ( like Waldinger is currently searching for).  Once again, I think it is possible that there are both types of POIS, and even a third one, thinking about the hormonal factors.   And, of course, a mix of all that is possible too.  But there are at least some cases where there is more at play than just the neurology of orgasm.  For example, there are POIS symptoms in members following a prostate leak caused by passing a large stool - no stimulation, no raise in neurotransmitters levels, just some prostatic liquid leaking in the urethra.  Also, there are cases of anorgasmic ejaculations leading to POIS  ( I, for one, had quite often anorgasmic ejaculations, and POIS is fully manifesting anyway, and have read similar reports by other members....  for me POIS should be called Post Ejaculatory Illness Syndrome, or PEIS.... ). Again, I am not again "pure neurological" POIS as a possibility, but would have to be a subtype of POIS.

Your stack of supplements reminds me a lot about what Kurtosis was taking for methyl cycle support.  He also tried SAMe, but was linking its effectiveness to improved methylation of histamine ( he had a 23andme genetic test done, and based his explanations on that, in part.  Did you have such a test done ? ).  You can see an example of his own theory at http://poiscenter.com/forums/index.php?topic=783.msg7183#msg7183 .  He had a very effective control of his symptoms, like you have too.

Some other members also report quite good results with Complex B vitamins, along the lines of your own stack ( but maybe minus the SAMe). 

I did not tried SAMe myself, it is rather hard to find here, and is also quite expensive here.  Since I have found an effective pre-pack composed of cheaper supplements, I have stopped at that and did not have to try SAMe.

Is there any particular reason why you advice to discontinue methylfolate ( B9) after a month ?

Also, quercetin, luteolin, and other mast cell stabilizers has been shown to be very useful and effective in my case and for other members as well.   I read you seems to avoid them, linking them to negative effect on sperm mobility.  Is it because you are in a relationship and try to have children ?  Because otherwise, sperm motility is not that important, and those mast cells stabilizers are a good add-on against the effects of histamine, so can be quite useful in POIS.  I do not write this to be critic, just to fully understand the reasons behind the opinions you express in your post.


Thanks again for sharing.  I fully agree with your idea of posting about our results and ideas, so we receive feedback, and all together, improve our understanding of POIS.

[nanna1]

Hi Quantum,

  Thanks for your detailed reply. As stated earlier, I wanted to open-source this stack so that others could build upon it, modify it, and improve it. I?m currently experimenting to find the optimum minimum dosages.

  The POIS forums have been very helpful in researching the POIS cascade. I used them as a guide to find the mostly likely causes and remedies of the disease and searched the literature to validate some approaches and discard others. For example, my initial reason for looking into and trying the B vitamins came from success stories here (POIScenter) from members who used them. However, I found that not all of the B complex vitamins are needed to see improvements in POIS. I recommended staying away from concentrated extracts of quercetin, luteolin, etc.. because I would like to have children some day and need a stack that will allow me to continue to be fertile. But I do consume foods with those plant nutrients in them (apples, onions, green tea). Niacinamide (vitamin B3) is the strongest mast cell stabilizer that you can buy over the counter (https://www.ncbi.nlm.nih.gov/pubmed/57931) and is used in skin beauty products for that reason. Nicotinic acid has the opposite effect. I recommended discontinuing B9 after a month because long term folate supplementation is associated with increased cancer risk.

  Background about me, I?m a postdoc working in the area of biomedical engineering. POIS is not my specialty area. My work/research focuses on gene regulation networks, receptor mediated gene expression, protein expression and their morphological consequences.

  You were right to point out that there is more than one type of POIS disease. According to the above POIS cascade hypothesis there are at least 3 types of POIS (COX, LOX and CYP450 mediated) and 2 causes (alpha1-receptor, h1-receptor overexpression). All three of these types result from AA being metabolized by these enzymes. And depending on our individual relative genetic expression of the three classes of enzymes, we should each experience a unique mixture of the three diseases. This does not exclude there being other types of POIS and additional cause.
A map of COX and LOX from: Dietary long-chain n−3 fatty acids for the prevention of cancer: a review of potential mechanisms. (2004) http://ajcn.nutrition.org/content/79/6/935.full

  I agree that inflammatory cytokines are downstream mediators of POIS. The initial focus for the stack was looking as far upstream as possible to get to the root cause. Since the elevation of norepinephrine is transient around the time of orgasm, the alpha1-adrenergic (a1A) receptor should only change blood pressure for a small window of time (reference #1 in above post). Histamine is a different story. As you and kurtosis have noted, histamine levels are brought down by SAM-e, and if SAM-e is depleted, the h1-histamine receptor can continue to be stimulated and modify blood pressure. So blood pressure may point to whether a1A or h1H is more of an individual?s problem. Thanks for bringing up the blood pressure issue. I had not thought about it before.

  As it relates to stool passing causing POIS, may I suggest a plausible explanation; the seminal vesicle. It is important to consider that the seminal vesicle sits on top of the prostate and rest against the colon (https://en.wikipedia.org/wiki/Seminal_vesicle). As the stool passes through the lower colon, it will compress the seminal vesicle before reaching the prostate. The most abundant lipid in seminal fluid is phosphorylcholine (https://en.wikipedia.org/wiki/Semen#Human_semen), which, in the absence of sufficient methyl groups, is generated from PC in the lipid bilayer using a POIS Cascade type mechanism. So whenever seminal fluid is drawn through the prostate, the body will naturally try to replace methyl groups from lost phosphorylcholine. No orgasm (requiring dopamine) is needed to trigger the above POIS; just the contraction of the seminal vesicle (requiring norepinephrine). The main job of the prostate is to keep the bladder and seminal vesicle from leaking. However, if the prostate is leaking, it is likely that one or both of the other two are as well. Again this is just a suggestion open to debate.

  I searched through the literature and found no mechanisms for antigen mediated POIS. The immune cells have access to the prostate. If there is enough antigen (or allergen) stored in the prostate to cause sickness, then I would expect the prostate would always be under attack by the immune system. I fully agree with the title rosscb used for the link you shared from kurtosis? post, ?The autoimmune theory is bogus?.

  Thanks again Quantum for sharing your insights and experience. Since I am a new member of POIScenter this was very helpful. Some of your questions were challenging and intellectually stimulating. Hopefully, the community benefits from this and further discussions!

[Quantum]

Hi nanna1,

I am not surprised to learn that you work in biomedical engineering.

About the autoimmune hypothesis, the jury is still out on this one, and I still think it can be part of what causes POIS  ( I was interested in Kurtosis post, in the thread I referred to, but not the OP opinion   ) .   My view on this is based on the fact that, beyond the existence of a testicular/urethral blood barrier, there is the very low blood flow in the prostate tissue.  This is well known, and explains why the antibiotic treatment for a bacterial prostatitis can last for as long as three months - the active ingredient penetrate very slowly in the prostate tissue, as well as the white blood cells that should have get rid of the infection in the first place.   So, it could be possible that the sudden and heightened exposure to prostatic fluid and a potential prostatic antigen in it, following ejaculation, could trigger an auto-immune reaction otherwise not possible.

But, as we already know, POIS medical study will be necessary to test those hypothesis, be it the neurological, the immunological or hormonal hypothesis. 

The fact that niacin is a very good mast cell stabilizers could explain why there are so many empirical success among members with it.  However, POIS is very complex, and for some unknown reasons,  a significant proportion of members have no relief with niacin ( hence my "POIS types chart", with many possible subtypes, based on specific relief methods).

Your explanation about POIS vs passing stool is well constructed, and is in line with my own opinion, that is, a local reaction occurs, in opposition to other general explanations of POIS that rely on the neurotransmitters variations in the brain during orgasm, exclusively.   So, either the local event is from prostatic or seminal glands fluid, I am at ease with that.  But I wouldn't subscribe to a "brain-only triggering event " theory.   

For further discussion, if you are interested, how would you tackle the "clusters of symptoms" problem, in your general hypothesis of POIS ?   In a given POIS sufferer, the symptoms are quite stable from one episode to the other.  But from one POIS sufferer to the other, some clusters may be present of absent.  For example, some have the "allergy-like" symptoms ( itchy eyes, sneezing, rashes, etc...) some not, and never had them.  Also, most have both cognitive and emotional symptoms ( cognitive impairment, and, personality and mood change, and not for the better....).   But in some case, like in myself and some others, I have much emotional symptoms, but absolutely no cognitive symptoms.   That's yet another "POIS riddle".  There is of course a question of personal reaction and genetics, maybe, common chain of event, but such difference is quite questioning.   I would be interested on your opinion on this  ( you may already have read, or not, my own view on this, but as you said, different points of view makes for a better overall vision ).

Thanks for this discussion!

 

[romies]

Hi nanna1,

Thank you for an very insightful write-up! I am glad that your regimen works very well for you.

I wonder if you could shed some light on some questions.

1. How many "o" per week can you have these days without any pronounced symptom? I assume that you are no longer on methylfolate supplements.

2. when you lift weight or exert yourself for 30+ mins, do you have a lite version of POIS-like symptoms?

From my personal experience, 5-HTP supplementation + IDO/TDO inhibitors are very important in my stack.  Taking NSAID alone (blocking COX-1/2) is not sufficient.
3. Any lead on how α1A and H1A may trigger IDO/TDO upregulation?

From my past discussion with Quantum, I think there is a large component of Mast Cell Activation in POIS, sometimes also called Mast Cell degranulation induced pseudoallergy. Many NSAID (aspirin, ibuprofen) actually activate mast cells more, e.g. in "aspirin induced asthma". I am taking celecoxib as needed because it also inhibits ALOX-5 and limits leukotriene production. Quercetin, Curcumin also help in these areas.

4. If a1A and h1H receptors were the main reasons, why not take a selective α1-adrenergic receptor antagonist or an alpha blocker, and a H1 antihistamine 30mins before your O. I wonder if you have tried that. On paper alpha blocker + h1 antihistamine would solve all the problems in your case, since they arrest the process from the very beginning?

Thanks!

[nanna1]

Hi Romies,

  Thank you for your question and comments. I number the responses to make sure I address all your questions. Please let me know if this is helpful or if you have any suggestions.

• Currently I O about twice a week. I don?t have any symptoms of POIS that I am aware of. Sometimes I feel really tired and sleep immediately following (probably low dopamine). But after a quick nap, I feel fine. I noticed that the day after, I am super motivated. I still take the supplement stack daily as described above.
• Lifting weights for me used to cause fever, sneezing and runny nose. Not as bad as orgasm though, which for me would include all of the above symptoms plus really bad headache and joint pain in random places. Vitamin B complex drastically reduced my exercise induce sickness. But I wasn?t healed of POIS until I introduced SAM-e and Benfotiamine (fat soluble vitamin B1).
• Romies, to be honest with you, before your question, I hadn?t looked into IDO/TDO. But I did a quick literature search and here is what I found. Both a1A and h1H upregulate IDO/TDO through the COX-1/2 enzymes. More specifically, (a1A & h1H)->Arachidonic Acid (AA)->COX->prostaglandin E2 (PGE2)->Interferon-γ-> IDO/TDO gene expression (please see references below) [1, 2]. Three of the supplements currently in the POIS Cascade stack suppress IDO/TDO usage and kynurenine production (vitamin D3, vitamin B6 and EPA).

• Vitamin D3 downregulates IDO/TDO expression by two independent methods. D3 blocks COX-1/2, and D3 blocks the genetic transcription of the Interferon-γ gene on the DNA itself [3].
• EPA (omega-3 fatty acid) blocks AA production, blocks AA incorporation into phosphatidylcholine (PC and phospholipid bilayer) and blocks AA access to COX/LOX/CYP450 enzymes.
• Vitamin B6 (along with other protein enzyme) converts tryptophan into serotonin. Another way of thinking about it is, B6 diverts tryptophan away from the IDO/TDO enzymes (tryptophan->IDO/TDO-> kynurenine) [5]. Which leads to a reduction in kynurenine [6]. Moreover, B6 accelerates the removal of kynurenine from the body by preventing the downregulation of the enzyme that removes kynurenine [7]. (please see figure below)

  Both D3 and EPA are fat soluble, so it may take a month of consistent supplementation to see their full effects. B6 is water soluble and should kick-in within a couple of days. Many of the supplements in the POIS Cascade Stack have slow diffusion across the blood/brain barrier and/or slow incorporation into the phospholipid bilayer. So it could take 3 to 4 weeks of consistent supplementation before the effects can be assessed. I personally have not tried IDO/TDO inhibitors, so any knowledge on prescription medications may best be addressed by a health healthcare professional.

  Mast cells have a dedicated pair of receptors that specifically detect niacinamide and nicotinic acid. Dietary niacinamide is probably the most potent inhibiter of mast cell activation that you can find for two reason. First, niacinamide alone has higher bioavailability than polyphenols like quercetin and curcumin which require black pepper extract to enhance their bioavailability. Second, niacinamide is one of the body?s own endogenous inhibitors of mast cell activation. The receptors for nicotinic acid have the opposite effect and cause niacin-flush (selective mast cell release). I have one warning about directly inhibiting mast cells. Mast cell activation is a natural part of orgasm (even for non-POIS people) and is required for ejaculation. Attenuation will necessarily lead to reduced ejaculate volume. I experienced this personally with curcumin, luteolin and niacinamide. The reason I stopped trying to directly inhibit mast cells is that I plan to impregnate my future wife and I want as much ejaculate as possible. My person preference of course, has nothing to do with the POIS disease or the pleasure of orgasm. With that said, I do not wish to discourage you or any others, who may have different goals than my own, from using mast cell inhibitors.

• 4. You are right, in theory drugs that block a1A and h1H should stop POIS. I have not tried any a1A inhibitors, but I have tried h1H inhibitors (Benadryl, Claritin, Allegra) with a lot of success. Benadryl worked the best; no sneezing, runny nose, joint pain or watery eyes. However, Benadryl has a lot of side effects; long-term use is associated with dementia. Claritin and Allegra were okay. Allegra has almost no side effects. But none of the h1H blockers completely got rid of my POIS headaches. Moreover, when I stopped taking the h1H inhibitors there seemed to be a rebound in the receptors. Once the drug wore off, I was even more sensitive to allergens like pollen than before. This ?rebound? happened with all three (Benadryl, Claritin, Allegra). From my experience, unless it addresses a root cause of POIS, a drug (or herb) that solves one problem will inevitably create others. But when you don?t know the root cause and you need short-term relief, definitely try anything that helps.
  

1.   A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation (2017)
2.   Interferon-gamma ? Inducible Inflammation: Contribution to Aging and Aging-Associated Psychiatric Disorders (2011)
3.   Interferon-γ Regulates the Proliferation and Differentiation of Mesenchymal Stem Cells via Activation of Indoleamine 2,3 Dioxygenase (IDO)
4.   Vitamin D3: a transcriptional modulator of the interferon-gamma gene. (1998)
5.   Serotonin a la carte: Supplementation with the serotonin precursor 5-hydroxytryptophan. (2006)
6.   A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites. (2013)
7.   https://en.wikipedia.org/wiki/Kynurenine_pathway#Acquired_and_inherited_enzyme_deficiencies

[romies]

I did not tried SAMe myself, it is rather hard to find here, and is also quite expensive here.  Since I have found an effective pre-pack composed of cheaper supplements, I have stopped at that and did not have to try SAMe.

Walmart Canada sells SAMe online at a pretty low cost. I am just thinking that SAMe could be an addition to your NE-morning-after stack. I noticed nanna1's stack does not have to be timed to his O's.

[LAPOISSE]

Hello nanna,

Thanks for your impressive work.

I've been thinking for a while now that POIS was psychologically rooted mainly because my personnal history could easily explain it.
I've got  a lot of help from meditation and as long as I keep my anxiety level low, POIS symptoms are managable.Symptoms are also almost absent when I am in vacation. Moreover, sometime I get symptoms (exhaustion, confusion, etc without orgasm while I can be symptoms free after an orgasm.
I've also had for years really usefull help with propanolol a beta blockers which inhibit sympathetic nervous system.
So it appears that-at least in my case but not only- the state of my nervous system(sympathetic = anxiety vs parasympathetic = calmness) has a major influence on the severity and duration of symptoms.
I still feel that there is a disregulation somewhere happening after  orgasm and anxiety itself doesnt seems to explain everything.

Is your theory can articulate with what I describe above ?

Thanks a lot

[romies]

Hi nanna1,

Thank you for your detailed reply. You clearly have thought a lot and done your research.

2. Lifting weights for me used to cause fever, sneezing and runny nose. Not as bad as orgasm though, which for me would include all of the above symptoms plus really bad headache and joint pain in random places. Vitamin B complex drastically reduced my exercise induce sickness. But I wasn?t healed of POIS until I introduced SAM-e and Benfotiamine (fat soluble vitamin B1).

I am curious here if your exertion-induced symptoms were also most severe 8-10 hrs after your exertion, and lasted for 1-2 days. That was my experience.

Romies, to be honest with you, before your question, I hadn?t looked into IDO/TDO. But I did a quick literature search and here is what I found. Both a1A and h1H upregulate IDO/TDO through the COX-1/2 enzymes. More specifically, (a1A & h1H)->Arachidonic Acid (AA)->COX->prostaglandin E2 (PGE2)->Interferon-γ-> IDO/TDO gene expression (please see references below) [1, 2]. Three of the supplements currently in the POIS Cascade stack suppress IDO/TDO usage and kynurenine production (vitamin D3, vitamin B6 and EPA).

I am familiar with the PGE2-Interferon-γ pathway. I was wondering if there is any other direct pathway.

• Vitamin D3 downregulates IDO/TDO expression by two independent methods. D3 blocks COX-1/2, and D3 blocks the genetic transcription of the Interferon-γ gene on the DNA itself [3].
• EPA (omega-3 fatty acid) blocks AA production, blocks AA incorporation into phosphatidylcholine (PC and phospholipid bilayer) and blocks AA access to COX/LOX/CYP450 enzymes.
• Vitamin B6 (along with other protein enzyme) converts tryptophan into serotonin. Another way of thinking about it is, B6 diverts tryptophan away from the IDO/TDO enzymes (tryptophan->IDO/TDO-> kynurenine) [5]. Which leads to a reduction in kynurenine [6]. Moreover, B6 accelerates the removal of kynurenine from the body by preventing the downregulation of the enzyme that removes kynurenine [7]. (please see figure below)

  Both D3 and EPA are fat soluble, so it will take about a month of consistent supplementation to see their full effects. B6 is water soluble and should start to kick-in within a couple of days. Romies, my recommendation would be to either supplement with these 3 or the entire POIS Cascade stack for a month (while continuing with your other meds). And then slowly wean off both 5-HTP and IDO/TDO inhibitors over the course of a week while continuing the stack. I personally haven?t tried IDO inhibitors so I don?t know how the weaning process will work. You could be the first to find out!

I am glad that Vitamin D3 and EPA worked for you to block COX/LOX, but they are not enough for me.
I have been taking daily supplement of the following for more than 5 years, years before I tried Quantum's prepack.
Methylguard (methylfolate 400mcg; methylcobalamin 400mcg; Trimethylglycine 600mg)
Vitamin D (4000IU)
Vitamin B6 5mg
Zinc 10mg (from Zinc Mono-L-methionine)
Mg 150mg (from Magnesium Aspartate)
EPA (410mg) + DHA(274mg)

These were not enough for me. Without Quantum's prepack, I will still get a 2-day POIS hell. 

I am still taking the stack above daily for other reasons, as suggested by my blood lab report.

I have not tried such a high EPA dose. I will give it a try with concentrated EPA/DHA, together with ALA, to really suppress AA synthesis.

The pre-pack is used as a one-time as-needed dose. So there is not much weaning here, fortunately. I sometimes go on 2 weeks without having an O or needing a prepack when I am busy/traveling.

  Mast cells have a dedicated pair of receptors that specifically detect niacinamide and nicotinic acid. Dietary niacinamide is probably the most potent inhibiter of mast cell activation that you can find for two reason. First, niacinamide alone has higher bioavailability than polyphenols like quercetin and curcumin which require black pepper extract to enhance their bioavailability. Second, niacinamide is one of the body?s own endogenous inhibitors of mast cell activation. The receptors for nicotinic acid have the opposite effect and cause niacin-flush (selective mast cell release). I have one warning about directly inhibiting mast cells. Mast cell activation is a natural part of orgasm (even for non-POIS people) and is required for ejaculation. Attenuation will necessarily lead to reduced ejaculate volume. I experienced this personally with curcumin, luteolin and niacinamide. The reason I stopped trying to directly inhibit mast cells is that I plan to impregnate my future wife and I want as much ejaculate as possible. My person preference of course, has nothing to do with the POIS disease or the pleasure of orgasm. With that said, I do not wish to discourage you or any others, who may have different goals than my own, from using mast cell inhibitors.

Again, I think you are a lucky man, in that niacinamide works for you. I have tried before without success, with 1500mg niacinamide a few hours before an O, and had no success in reducing POIS symptoms. Niacinamide has a serum half-life of 6-7 hrs, so it should have still been in my system when I had an "O".

If you want to increase ejaculate size, there are some other supplements that reportedly work very well.
https://www.thundersplace.org/male-supplements/holy-grail-of-cum-load-increase.html

4. You are right, in theory drugs that block a1A and h1H should stop POIS. I have not tried any a1A inhibitors, but I have tried h1H inhibitors (Benadryl, Claritin, Allegra) with a lot of success. Benadryl worked the best; no sneezing, runny nose, joint pain or watery eyes. However, Benadryl has a lot of side effects; long-term use is associated with dementia. Claritin and Allegra were okay. Allegra has almost no side effects. But none of the h1H blockers completely got rid of my POIS headaches. Moreover, when I stopped taking the h1H inhibitors there seemed to be a rebound in the receptors. Once the drug wore off, I was even more sensitive to allergens like pollen than before. This ?rebound? happened with all three (Benadryl, Claritin, Allegra). From my experience, unless it addresses a root cause of POIS, a drug (or herb) that solves one problem will inevitably create others. But when you don?t know the root cause and you need short-term relief, definitely try anything that helps.

For me, the daily Methylguard (methylfolate 400mcg; methylcobalamin 400mcg; Trimethylglycine 600mg) cleared the histamine in my body effectively. I used to need daily Zyrtec for nasal allergy before I tried Methylguard, but I don't need Zyrtec any more with Methylguard.

I suspect that your subtype of POIS is somewhat different from mine, because Zyrtec/Claritin/Allegra never gave me cognitive/mood relief from POIS.

[romies]

Regarding the effects of Curcumin, Quercetin on sperm motility

The papers that says curcumin reduces sperm motility were largely performed NOT with oral-intake of curcumin. Instead, curcumin was mixed into semen directly. See the following discussion:
http://natural-fertility-info.com/fertility-health-clearing-up-confusion-about-turmeric-as-birth-control.html
https://www.ncbi.nlm.nih.gov/pubmed/21337449

And there are other study showing curcumin beneficial for sperm quality
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312379/
https://www.ncbi.nlm.nih.gov/pubmed/25149981

So maybe the jury is still out there.

[Quantum]

I did not tried SAMe myself, it is rather hard to find here, and is also quite expensive here.  Since I have found an effective pre-pack composed of cheaper supplements, I have stopped at that and did not have to try SAMe.

Walmart Canada sells SAMe online at a pretty low cost. I am just thinking that SAMe could be an addition to your NE-morning-after stack. I noticed nanna1's stack does not have to be timed to his O's.

Hi Romies,

Indeed, I have checked on walmart.com and prices are getting lower than a few years ago ( not on walmart.ca, though...).  I have also checked on vitacost.com, my preferred source for supplements not available in Canada, and prices for SAMe are lower there as well. 

I saw there are mainly 200mg and 400mg forms, and some are enteric coated.

Nanni, it would be of interest for the members here to know if the 200mg SAMe tablets you have been using are regular tablets or enteric coated tablets, and to confirm that your total daily dose is 200mg.

[Quantum]

2. Lifting weights for me used to cause fever, sneezing and runny nose. Not as bad as orgasm though, which for me would include all of the above symptoms plus really bad headache and joint pain in random places. Vitamin B complex drastically reduced my exercise induce sickness. But I wasn?t healed of POIS until I introduced SAM-e and Benfotiamine (fat soluble vitamin B1).

Very interesting, Nanni.   Last year, we had a thread about "pseudo-POIS" symptoms after physical exercise.   Romies has this problem, and I have too (mostly marked fatigue, and my recovery period is abnormally long - but not all the other usual POIS symptoms I have ).  I take a simpler version of my pre-pack before sport, that includes the same omega-3 source ( 600mg EPA/300mg DHA), some anti-oxidants too.  I also take potassium and some other supplements after sport ( but potassium seems to be linked to a very personal condition, I seem to be the only one to have good results with it, be it for POIS or after sport).

It is clear that no semen production is implied in sport ( I enjoy sport, but not that much...hehe...), so this is where your hypothesis about AA production following high norepinephrine levels could be a good explanation.   

I hope the upcoming team that will receive our research grant for a POIS study will tackle such subjects as inflammatory cascades and metabolic changes in POIS.   For now, all we have is some empirical success, and we have to deduct what is really going on from what has brought some relief.   

[romies]

I saw there are mainly 200mg and 400mg forms, and some are enteric coated.

According to Examine.com https://examine.com/supplements/s-adenosyl-methionine/#summary2-0

enteric coated capsules increases bio-availability by ~3x.

[romies]

---eicosapentaenoic acid, EPA (1000mg) [AA synthesis inhibitor, AA blocker]
---docosahexaenoic acid, DHA (260mg) [AA synthesis inhibitor]

Just noticed that your daily intake of EPA+DHA is 3x of what I am typically taking. I will try this for 60 days and report my findings.

[romies]

2. Lifting weights for me used to cause fever, sneezing and runny nose. Not as bad as orgasm though, which for me would include all of the above symptoms plus really bad headache and joint pain in random places. Vitamin B complex drastically reduced my exercise induce sickness. But I wasn?t healed of POIS until I introduced SAM-e and Benfotiamine (fat soluble vitamin B1).

Very interesting, Nanni.   Last year, we had a thread about "pseudo-POIS" symptoms after physical exercise.   Romies has this problem, and I have too (mostly marked fatigue, and my recovery period is abnormally long - but not all the other usual POIS symptoms I have ).  I take a simpler version of my pre-pack before sport, that includes the same omega-3 source ( 600mg EPA/300mg DHA), some anti-oxidants too.  I also take potassium and some other supplements after sport ( but potassium seems to be linked to a very personal condition, I seem to be the only one to have good results with it, be it for POIS or after sport).

What is your baseline daily EPA/DHA intake besides the pre-packs?

Here is some good reading with referenced summary (page 48, 49): https://books.google.com/books?id=v6fuDQAAQBAJ&lpg=PA1&dq=enteroimmunology&pg=PA48#v=onepage&f=false

My take away is
1. Flaxseed oil does not work, since ALA supplementation does not suppress AA formation. see graph on page 46
    also flaxseed oil oxidizes way too fast.
2. Oliver oil is good, with low LA load. Just need to be taken with fish oil.
3. It takes 60 days for EPA to reach steady state in ones body.
4. If our COX, ALOX, a1a, H1a are too trigger happy, we may need to be aggressive on EPA/DHA. So I am looking at 2 gram/day in take. That would reduce DOMS too.

[Quantum]

What is your baseline daily EPA/DHA intake besides the pre-packs?

Here is some good reading with referenced summary (page 48, 49): https://books.google.com/books?id=v6fuDQAAQBAJ&lpg=PA1&dq=enteroimmunology&pg=PA48#v=onepage&f=false

My take away is
1. Flaxseed oil does not work, since ALA supplementation does not suppress AA formation. see graph on page 46
    also flaxseed oil oxidizes way too fast.
2. Oliver oil is good, with low LA load. Just need to be taken with fish oil.
3. It takes 60 days for EPA to reach steady state in ones body.
4. If our COX, ALOX, a1a, H1a are too trigger happy, we may need to be aggressive on EPA/DHA. So I am looking at 2 gram/day in take. That would reduce DOMS too.

Hi romies,

I took, in the past, EPA/DHA daily for many years, at around 400mg EPA/200mg DHA once or twice daily.  But a few years ago, when I turned to the "pre-pack" strategy, I stopped daily uptake of omega-3.  It ends up now that I take them around 2 to 3 times a week anyway, because my 600/400 capsules are part of both my sport pre-pack and my POIS pre-pack.


Regarding Flaxseed oil capsules, my reason for including them in my pre-pack is for the lignans in them, which are good antioxidants, and, mainly, have NMDAr blocking properties, so they protect against excitotoxicity, and thus reduces the POIS-induced anxiety and other CNS symptoms.

I do not consider flaxseed to be the most important part of my pre-pack, but who knows.  I could try only one capsule of flaxseed instead of 2, in my POIS pre-pack, and 2 capsules of omega-3 instead of one.   I did not made many changes or many new tests in the last two years.... if it's not broken, don't fix it

[nanna1]

Hi All,
Here is how I source my stack:

• NOW SAMe 200 mg,60 [enteric coated] Tablets (https://www.amazon.com/NOW-SAMe-200-60-Tablets/dp/B0013OW3V6/ref=sr_1_21_s_it?s=hpc&ie=UTF8&qid=1501024535&sr=1-21&keywords=sam-e)
• Nature Made Vitamin D3 2000 IU, Value Size, 220-Count (https://www.amazon.com/Nature-Made-Vitamin-Value-220-Count/dp/B004U3Y8NI/ref=sr_1_6_s_it?s=hpc&ie=UTF8&qid=1501024866&sr=1-6&keywords=d3&th=1)
• NOW Alpha GPC 300 mg,60 Veg Capsules (https://www.amazon.com/NOW-Alpha-GPC-300-Capsules/dp/B001RYKA3U/ref=sr_1_5_s_it?s=hpc&ie=UTF8&qid=1501024705&sr=1-5&keywords=alpha%2Bgpc&th=1)
• Life Extension Mega Benfotiamine, 120 capsules (https://www.amazon.com/Life-Extension-Mega-Benfotiamine-capsules/dp/B000OSIO9W/ref=sr_1_2_s_it?s=hpc&ie=UTF8&qid=1501024996&sr=1-2&keywords=mega%2Bbenfotiamine%2B250%2Bmg&th=1)
• Nordic Naturals - EPA Xtra, Promotes Mood and Heart Health, and Optimal Immune Function, 60 Soft Gels (https://www.amazon.com/gp/product/B002CQU4Z6?ref_=sr_1_3_a_it&qid=1501023857&sr=8-3&keywords=EPA&pldnSite=1&th=1)
• OmegaVia EPA 500. Pharmaceutical Grade EPA Omega-3. Triglyceride-form EPA-only formula, 120 Capsules. 500 mg EPA per pill (https://smile.amazon.com/OmegaVia-Pharmaceutical-Omega-3-Triglyceride-form-Capsules/dp/B00D37S0HC/ref=sr_1_4_a_it?ie=UTF8&qid=1501040461&sr=8-4&keywords=epa)

Update/disclosure:

• I know I mentioned that I only supplement SAM-e once a day, but on O days I sometimes supplement a second time.
• I have increased my EPA (omega 3) supplementation to three times a day.
• Also, I drink a ?5-hour energy? drink two or three times a week to stay alert at work. It is my substitute for coffee since I do not drink coffee. I do not consider 5-hour energy as part of my stack because I drink it so rarely, but it does include B-vitamins and choline (methyl donor). So I thought I should mention that.

I am looking for a cheaper source of alpha-GPC (choline). Maybe a bulk power. If find one please let me know. [Choline bitartrate messes up with my stomach.]

  Thanks Romies for sharing that link on volume from Thunderplace. I might get some zinc arginine. Quantum, I thought your joke about liking/not-liking sports was LOL. There was a lot of good discussion and ideas from yesterday and today. I may not know the answers to some of the things that were brought up, but there was a question from Lapoisse about non-O stress related POIS-like symptoms. Since Quantum also found that managing stress helped control POIS (My method for prevention and control of my POIS symptoms - 80% to 100% effective), I thought I would do some digging. It seems like Quantum was really on to something with the NMDA inhibitors in his pre-stack.

  Stress up regulates histamine production in mast cells [1], and it up-regulates NMDA receptors (NMDAR, glutamate receptor) throughout the brain [2, 3]. Stress hormones like cortisol up-regulate the number of NMDAR through the glucocorticoid receptor [3]. Stimulation of NMDAR by glutamate causes the release of Arachidonic Acid (AA) from the phospholipid bilayer in the same way that alpha1-adrenergic (a1A) and h1-histamine (h1H) do; through activation of the enzyme Phospholipase A2 [4, 5]. The title of this article is worth noting: [NMDA receptors activate the arachidonic acid cascade system in striatal neurons. (1988)]. It is believed that abnormal NMDAR-mediated AA release is at least partly associated with inflammatory brain diseases. For example, mania and bipolar drugs like lithium, carbamazepine and valproate all inhibit Phospholipase A2 (and AA release) [6, 7]. The anti-depressant, lamotrigine, also inhibits Phospholipase A2 [6]. Antipsychotics, olanzapine and clozapine inhibit Phospholipase A2 (and AA release) [7].  In the following article, they note that COX mediated inflammation is decreased with all of these drugs: [Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. (2014)] Each of these drugs have other therapeutic effects specific to the diseases that they treat, but the one common benefit is inhibition of NMDAR->AA mediated inflammation.

  With that said, things get more complicated from here, because, like the adrenergic and histamine receptors, there are different NMDAR subtypes (NR1, NR2A, NR2B, NR3A, etc?). They each have different responses to different agonist and antagonist, and I am not sure which ones are associated with abnormal AA release/inflammation. It is known that glucocorticoids like cortisol down-regulate NR2A-NMDAR and up-regulate NR2B-NMDAR signaling [8]. While niacinamide (vitamin B3) has the reverse effect up-regulating NR2A-NMDAR and down-regulating NR2B-NMDAR. Agmatine Sulfate (which you can find on Amazon.com or GNC) is a pretty strong inhibitor of NR1-NMDAR, which might be helpful since AA & histamine themselves are enhancers of NR1 activation. (see figure below [9])

  Final note: It appears that stress hormones are what cause the NMDA receptors to become overexpressed and lead to abnormal inflammation. If we could keep those hormones in check, that would prevent the AA cascade. But this is the limit of my knowledge on the stress related aspect of a POIS cascade-like hypothesis. I found Quantum?s post that I referenced above useful looking at way to combat this. He includes some NMDAR blockers and several techniques of managing/reducing stress.


1.   Acute stress modulates the histamine content of mast cells in the gastrointestinal tract through interleukin-1 and corticotropin-releasing factor release in rats. (2003) (http://www.pnas.org/content/106/33/14075.full.pdf)
2.   Stress-Induced Changes of Hippocampal NMDA Receptors: Modulation by Duloxetine Treatment (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037916)
3.   Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory (2009) (http://www.pnas.org/content/106/33/14075.full.pdf)
4.   NMDA receptors activate the arachidonic acid cascade system in striatal neurons. (1988)
5.   NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. (1992)
6.   Mood-stabilizers target the brain arachidonic acid cascade. (2009)
7.   Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. (2009)
8.   Glucocorticoid Rapidly Enhances NMDA-Evoked Neurotoxicity by Attenuating the NR2A-Containing NMDA Receptor-Mediated ERK1/2 Activation (2010)
9.   Allosteric Receptor Modulation in Drug Targeting (2006)