As the
mu-opioid receptor (MOR) involvement seems very likely in a great part of POIS sufferers and is an ongoing discussion I also looked into the matter as it also looks likely in my case. What struck me first that there are many people who get better from
opioid agonists - enhancer (Tramadol, Tianeptine, THC, CBD, nicotine, other drugs), while others get better from
opioid antagonists - inhibitor (Low Dose Naltrexone) and depending on which side you are you can feel worse from the other at least theoretically, but maybe still is the reason why some of you feel worse of them who actually tried it. By the way opioid antagonists don’t actually inhibit endogenous opioids from being released into our body they just prevent them from linking to opioid receptors so they can’t express their main opioid effect. It also makes me wonder how much symptoms resemble (although not all) to
opioid intoxication (I am a possible antagonist. I mean I would possibly get better form antagonists. - see later), or in other cases to
opioid withdrawal (the agonist team possibly). It is also possible that there is a division regarding
MOR (mu-opioid) and KOR (kappa-opioid) and also delta and nociceptin opioid receptor (DOR and NOR) may be considered just to make things even more complicated.
https://en.wikipedia.org/wiki/Opioid_use_disorder#Symptoms_of_withdrawalI also noticed that many here try
Tramadol, but not
Tianeptine which seems a more reasonable choice as it is a good mu-opioid agonist (enhancer). It seems a far better option as it is cheap, safe and has few side effects, so I don’t see why anyone would rather go with THC or Tramadol. I would advise anyone who has positive experience with mu-agonists should at least give it a try if one can get a prescription of course.
Loperamide: A peripherally acting ?-opioid receptor agonist used to treat diarrhea. Could be considered as an anti-PAMORA (see below).
As Muon pointed out Loperamid seems to have worked for some IBS patients whose symptoms were worse after sexual activity. This might support my theory for POIS primarily having a GI origin and also raises the possibility for PAMORAs to be working well for some even though they don’t have a direct CNS effect, but this doesn’t necessarily mean it can’t have an indirect positive one.
https://poiscenter.com/forums/index.php?topic=2301.msg34333#msg34333I am in the
testosterone group, but I also think
Naltrexone would help me. Naltrexone’s most frequent side effect supposedly is a slightly bloody stool which can reduce with time. I also had a similar experience when I was under Zoloft deprivation and undergoing serotonin deprivation syndrome. At that time my POIS miraculously almost completely disappeared for a day and the most noticeable side effect was a slightly bloody stool. I think I had some unusual pain too, which might be the effect of the missing (at least reduced quantity) endogenous opiates. I know it is scary, but I had also been so clear in thinking than never in my life. There must be a connection here, so I would really like to test LDN. The only problem is its unavailability unfortunately.
Actually I was really surprised when I found that
endogenous opioid peptides (EOP) (like ?-Endorphin) are also produced in the
testis and particularly in the same
Leydig cells in which
testosterone is produced and they can also be produced
in different compartments of the male genital tract. Their contribution to disease pathology is extremely likely, but I am a bit confused about their relation to testosterone at this point. At least gonadotropin and luteinizing hormone (LH) seems to play a role in this.
https://academic.oup.com/endo/article-abstract/115/4/1645/2539019https://academic.oup.com/endo/article-abstract/124/4/1697/2531918https://www.karger.com/Article/Abstract/124049https://www.sciencedirect.com/science/article/abs/pii/0022473189901556https://academic.oup.com/endo/article-abstract/125/2/957/2532387There are some other mu-opioid (also KOR and DOR) antagonists:
- Naloxon is a non-specific antagonist – I think it should still work, but with more side effects. Its greatest problem is its very short half life, which is only 30 minutes.
-
Low Dose Naltrexone is a good candidate, but its unavailability is a great problem. Its half life is only a few hours which can also be a problem.
-
Samidorphan (SAM) is still under trial as a new kind of antidepressant, but it seems it has problems getting permission. It supposedly has even fewer side effects as naltrexone and its half life is the longest with 7 hours and is present in the body up to 24 hours.
As POIS is a chronic disease in my perspective it is one of the best candidate we can wish for. I hope they soon do something about it and begin producing it in small doses (LDS).
Samidorphan is a MOR antagonist, but on KOR and DOR it has agonistic effect, although
Buprenorphine/samidorphan combination seems to show especially good KOR antagonistic effects.
As naltrexone seems a good candidate against COVID-19 I think they should also test Samidorphan (SAM), as it may get its permission underway for the benefit for us at least hopefully.
https://en.wikipedia.org/wiki/Naltrexonehttps://en.wikipedia.org/wiki/SamidorphanPAMORAs: peripherally acting ?-opioid receptor antagonists. They only effect the MOR in the gastro intestinal (GI) tract and not in the CNS, but affecting the GI problems in a positive way they still might contribute to CNS symptom reduction. I think their consideration should be worthwhile.
Some PAMORA are:
Methylnaltrexone, Alvimopan (Entereg), Naldemedine, Naloxegol.
Some PAMORA if they actually work might even prove better than general MOR antagonists as they usually have a much longer half-life and thus an extended effect.
As MOR has an effect on bowel movement it seems likely that its any kind of
disruption (like opioid intoxication or withdrawal) may also have a great effect on the
butyrate equilibrium (homeostasis) just like
5-HT (serotonin) has and this has kind of a lot of implications too.
Someone here also mentioned that he felt worse of
LDN and Modafinil (Provigil) too. He might be in the agonist group. Also Modafinil is an inducer of the
CYP3A4 enzymes which are responsible for toxin and drug removal. Might it mean that it is very good for someone in the antagonist group (like me). Also
grapefruit and pomegranate inhibits CYP3A4 enzymes which might (or might not) be good for those in the agonist group. Actually
SJW also induces CYP3A4 enzymes which seems very good as it can have a dual positive effect with
amentoflavone for antagonists. Other inhibitors that caught my eye are
cannabidiol, milk thistle, niacin (vitamin B3), ginkgo biloba, piperine (black pepper), sesamin (sesame oil). For other inducers and inhibitors see the wikipedia page:
https://en.wikipedia.org/wiki/CYP3A4Kappa-opioid receptor (KOR) involvement also cannot be ruled out and in some cases (like mine) it even seems likely.
Amentoflavone is a naturally occurring non-selective kappa-opioid receptor (KOR) antagonist. I have to mention that
St. John’s Wort (SJW) also contains it, of which some have written to be very effective in reducing POIS. Someone here also mentioned that
chamomille contains apigenin in great amounts, which is actually a KOR antagonist (inhibitor). Some
medicinal mushroom capsules may also contain high amounts of apigenin extract (which worked for me).
Menthol is a naturally occurring KOR agonist (enhancer) and if I remember well
peppermint tea had a bad effect on me, but I will retest it later just to be sure.
https://en.wikipedia.org/wiki/%CE%9A-opioid_receptorActually Xin et al. hypothesized that while MOR agonists mediate
hyperthermia (maybe those who can’t stand hot showers), KOR agonists, such as
dynorphin, mediate
hypothermia (I just love a hot bath after O). Dynorphins also control
appetite (I become very hungry right after O) and
circadian rhythms.
Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals, so the effectiveness of
SNRIs on mood might also be explained this way.
So as things are it seems that dynorphin might be the “toxic compound” I have been looking for or is it? Can it actually cause all the symptoms and the disregulation of the butyrate equilibrium in itself or are there
concomitantly released compounds as well that further aggravate problems?
Are supposed dynorpins get adsorbed by charcoal or Chlorella (see below) or if not then what is?
Actually Lai et al. found that
dynorphin acts on the bradykinin receptor as well as KOR. As bradykinin can
induce vascular hyperpermeability this may also lead to a whole lot of toxins released and further immunological implications. This also means that in such a case opioid receptor antagonism would only partially abate symptoms as bradykinin receptor activation might still occur. In my case it would possibly explain why I developed sore throat and chest pain taking medicinal mushroom capsules with apigenin extract (see below) even though KOR inhibition occurs, but bradykinin may be upregulated.
https://en.wikipedia.org/wiki/DynorphinI also have to wonder if there are really more groups then how would my blacklist foods effect someone in an opposite group (like KOR agonist food in a KOR antagonistic group). Would they become better? Could someone confirm this? If so then would it also mean that my
blacklist foods have previously unknown opioid agonistic effects. Well I wouldn’t be surprised at poppy seed as it might contain trace amounts of opioid alkaloids, but I can’t imagine that the other foods like apricot, apple, sour cherry, sour cabbage, paprika, banana, etc. would have the same property, or actually do they?
Codein (prodrug for opioid agonists) might be another thing indicated as in animal studies they found that it may act as a natural neurotransmitter or neuromodulator in the central nervous system. I mention this as many medications affecting codein have been found to work in POISers. Codein is also often mixed with other medicine like
paracetamol, aspririn, ibuprofen, antisistamines, phenacetin, naproxen, indomethacin, diclofenac, caffeine, etc which can complicate symptom impact if one is either in the agonist or antagonist group.
CYP2D6 inhibitors should also be considered as a possible therapeutics for those on the antagonist side. Some of them are
paroxetine (Paxil), fluoxetine (Prozac), diphenhydramine (Benadryl), bupropion (Wellbutrin also known as Zyban), rifampicin, dexamethasone, etc.
https://en.wikipedia.org/wiki/CodeineAs a seemingly
over-activated KOR type (opioid agonists seem to work) I give a reference about the other medicines that worked for me (I took these more than 10 years ago and was not very knowledgeable at the time so I can’t go into detail.):
-
Zoloft (SSRI) noticeably shortened acute POIS, but didn’t cease POIS actually. Its intake was also not timed to O, so a better effect might have been achieved otherwise. As I mentioned Zoloft deprivation had the best effect, as POIS almost completely but only transiently disappeared. I also took
other kinds of SSRIs, which also worked similarly. Unfortunately I can’t really remember it in much detail.
-
Venlafaxin (SNRI): Checking my medical papers I supposedly was not only better, but also feeling better. I only took it for a short time as they switched it out to try something else.
-
Medicinal mushroom mix capsules: Some symptoms were better, some were enhanced. If I remember well I had much more energy and reduced muscle pain, GI symptoms were reduced, burning feeling at nose reduced, but on the contrary throat would often ache and chest pain developed more frequently. I also often had nocturnal emissions (aphrodisiac effect) due to it and I had a suspicion that it made me susceptible to developing a tonsillitis too. I had just rechecked and the capsule that worked for me contains mainly
fungal polysaccharides, also green tea extract (Epigallocatechin gallate – 5mg) and chamomille extract (apigenin - 9 mg). -
charcoal: the
pill form has a noticeable positive effect, although I also get a gut pain and constipation (although not by definition). Taking the
capsule form has a profound effect on POIS as all symptoms (even GI symptoms) get reduced to almost non-existent for a few hours. Unfortunately after this symptoms slowly reemerge and as a backlash I get a severe gut-ache and constipation for about two days which practically makes it unusable even if it has such a good effect. Based on this I tried
silicium-dioxide capsules, but they only had a very slight effect. Some here also wrote of the positive effects of
Chlorella which seem to have great
absorptive potential. I haven’t managed to try it yet but seems worthwhile.
Very recently I wanted to recheck my experiences with SSRIs, but as I couldn’t go to a doctor I began to take supplements instead.
-
Tryptophan: Its effects and side effects are almost the same as SSRIs. At 1 x 500 mg it only barely has a noticeable effect. At 2-3 x 500 mg (1000-1500 mg) its positive effect really starts to show. Its effect is especially good if taken 1 hour before O and in an hour after O. At 4 x 500 mg side effects begin to show, like sometimes feeling touched on the top of the head or blacking out for a few seconds when standing up. So it has the most positive effects at 3 capsules (morning-noon-evening and also somewhat timed to O). These are: my blurry vision and foggy mind cleared up, red eye symptom reduction. Well I still see the red veins in my eye, but it looks like they can’t burst or leak out actually. As
serotonin is a potent vasoconstrictor this might explain this. The burning feeling at the nose disappeares, but I also become prone to sneezing. As a side effect I also gained almost total control over ejaculation, actually I can do it for hours if I wish, which is kind of a great step-up. Meanwhile some GI symptoms (the burning and itching feeling to be exact) also got worse. I suspect a high dose also enhances dry eye symptoms in the evening, and although I can sleep easily, but when I wake up in the middle of the night I can’t seem to be able to sleep again.
-
MACA (testosterone enhancer): It has a profound effect on POIS. When I take a 1 x 600 mg capsule and wait about 2 hours my blurry vision and thinking suddenly clears up. It also reduces all other symptoms. It doesn’t have such a good effect on all symptoms as tryptophan, but it also seems to reduce the burning effect of the GI symptom. It can also contribute to a longer masturbation, but not as much as tryptophan. Although maca+tryptophan seem to have an incredible effect on sexual capability, but I advise caution as in my experience one can get a severe heart ache after a few hours (it might be only natural backlash) and even I try to avoid it now. I think I went up to 4 or 5 capsules a day, but its effect seems to have an upper limit, so now I only take one in the morning and one in the evening.
Tribulus terrestris pills (also 600 mg) also seem to work similarly, but it has a reduced effect, which might also be due to the
pill and capsule difference as with charcoal.
-
Cetirizine-EP 10 mg (
weak antihistamine with few side effects): So far this is the only antihistamine that I tried. I also haven’t used it separately, but it seems to raise the effect of MACA. It also reduces the GI symptoms.
In addition to this I have also found that
ginger can further boost the combined MACA and Cetirizine duo noticeably.
So my current regime:
-morning: 1 x MACA capsule, 1 x Cetirizine
-somewhat after noon: 1 x tryptophan, 1 x Cetirizine
-evening: 1 x MACA, 1 x Cetirizine
Of course if I want to masturbate I also take one or two more tryptophan and/or maca capsules.
Although the
symptom reduction is great (about 70-80%), I still feel the effect of POIS and it also seems to me that
the symptom reduction in the chronic phase is weaker (might only be subjective) as I can still perceive the wave like fluctuation of the symptoms. This regime seems to be able to reduce the enhancing effect for some food, but not for others. This of course needs to be tested a lot more as I am not even certain of the effect of some food types under normally ill circumstances.
Plans:
1. Seek as much KOR and/or MOR antagonists as I can and rigorously test them individually and in combination.
2. Testing Tianeptine should be interesting in my case, as it is only a MOR agonist (also delta), but not a KOR agonist, so the modulation of each symptom would be very informative.
3. I also want to test Chlorella for its potential adsorptive effect and hopefully less side-effect than charcoal.
4. In relation to codein testing CYP2D6 inhibitors seems worthwhile.
5. Testing CYP3A4 inducers also seem meritable.
6. I haven’t tried pseudoephedrine yet and would really like to know its effect on me.
Further considerations:
Following an ejaculation event my
desire for sex seems to be the highest after 1-2 weeks (when acute symptoms vane) than begins to decrease. This might also indicate an opioid (sex) withdrawal as I have been always regarding this as a malicious cycle of sex addiction that is really hard to overcome without release which of course starts it anew.
