Author Topic: Does POIS result from overstimulation of muscarinic receptors  (Read 12198 times)

BluesBrother

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Does POIS result from overstimulation of muscarinic receptors
« on: January 17, 2016, 03:47:52 PM »
I am wondering whether POIS can be the result of overstimulation of muscarinic receptors. Let me explain:

The research by Prof. Komisaruk as well as recent discussions on this forum revolve around the role the vagus nerve might play for POIS. I was reading about the relationship between the vagus nerve and ejaculation.

Ejaculation and muscarinic receptors

The vagus nerve "communicates" with smooth muscles and organs by releasing the neurotransmitter Acetylcholine (ACh). Acetylcholine binds to two kinds of receptors: nicotinic and muscarinic. What does that have to do with ejaculation? First of all, the neurological mechanism behind ejaculation is not yet fully understood - but "pharmacological evidence relating to a cholinergic mechanism for both contraction and secretion of prostate and seminal vesicle exist [70, 91, 99]. Essentially, these glands were activated by cholinomimetic compounds acting on muscarinic receptors [49]" (Giuliano and Clement, 2013).

Here is the abstract from a study on rodent models (Gil et al., 2000):

"The effects of muscarinic receptor stimulation were tested on the urethro genital reflex (UGR) in anesthetized and spinal cord-transected rats. Drugs were applied directly to the spinal cord. The electromyographic activity (EMG) of the bulbospongiosus (BS) muscle was used for recording UGR. In six animals BS as well as soleus, posterior biceps or peroneus tertius muscle EMG was recorded simultaneously. Muscarine (5, 10, 20, 50 and 100 μg) was applied in 22 animals after cutting L6?S1 dorsal roots. Some observations were made on another six animals, to which an extensive bilateral dorsal rhizotomy (L3?S2) was performed. Rhythmic bursts of similar frequency and size to those seen during UGR were found in BS muscle a few minutes after muscarine application. No rhythmic bursting was found on the hindlimb muscles, but exclusively on BS muscles. The effects of homatropine (25, 50, 100 and 200 μg), an acetylcholine muscarinic receptor antagonist, were tested in 21 rats after UGR was elicited three times at low stimulation intensity (7 mm Hg). Homatropine produced two effects: (i) A significant increase in the latency of UGR. (ii) A facilitation of UGR inhibition. In view of these results it can be speculated that muscarinic receptor stimulation is involved in the elicitation of UGR."

Symptoms of muscarinic receptor overstimulation

For now let us take as given that stimulation of muscarinic receptors plays a role in ejaculation. Why could this matter for POIS? Here are the symptoms of OVERstimulation of muscarinic receptors (see http://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=9 , see also: (https://en.wikipedia.org/wiki/SLUDGE_syndrome)


Respiratory tract

- bronchorrhea (thick, mucoid secretions)
- bronchospasm
- chest tightness
- dyspnea
- productive cough
- rhinorrhea

Eyes

- blurred vision (especially, difficulty focusing on near objects)
- conjunctival injection
- dimness of vision
- miosis (pupillary constriction)

Gastrointestinal tract

- cramping
- diarrhea
- incontinence
- nausea
- vomiting

Urinary tract

- incontinence
- urination

Cardiovascular system

- AV block
- bradycardia
- hypotension
- idioventricular rhythm
- ventricular dysrhythmias (torsades des points)

Exocrine glands

- hyperamylasemia
- lacrimation
- salivation

Many of these symptoms also occur in POIS. Overstimulation of muscarinic receptors is rare and usually occurs after contact with pesticides. However, POIS is rare as well, and maybe overstimulation of muscarinic receptors could be involved in its mechanism.

More evidence

There is more evidence:

At least two users on this forum (Outsider, FloppyBanana) have eliminated or reduced their POIS symptoms by taking Mytelase (https://en.wikipedia.org/wiki/Ambenonium_chloride). Mytelase is a cholinesterase inhibitor - the drug inhibits the breakdown of the ACh, the neurotransmitter which binds to muscarinic receptors. The concentration of ACh between neuron and receptor thus increases - and one might think that it might lead to more stimulation of the receptor. However, this does not have to be the case. From https://en.wikipedia.org/wiki/Acetylcholinesterase :

"For a cholinergic neuron to receive another impulse, ACh must be released from the ACh receptor. This occurs only when the concentration of ACh in the synaptic cleft is very low. Inhibition of AChE leads to accumulation of ACh in the synaptic cleft and results in impeded neurotransmission."

To repeat:
A cholinesterase inhibitor can thus lead to LESS stimulation of cholinergic receptors (of which one group are muscarinic receptors). It could thus be that Metylase helps in POIS because it downregulates stimulation of muscarinic receptors.

There is yet more evidence:

Many of us suffer from premature ejaculation. (Over)stimulation of muscarinic receptors could cause this. Studies in rodents have found that treating the animals with muscarinic agonists (hence stimulation of muscarinic receptors) decreases time to ejaculation.

Gil et al. (2000) write "also, it has been suggested that acetylcholine may play a role in the phenomenon of premature ejaculation [2]." They quote Ahlenius and Larsson (1985) who write "It is possible, however, that the antimuscarinic effects
of thioridazine and chlofimipramine are responsible for the effects of these drugs on time to ejaculation. Available evidence indicates that both activation and blockade of muscarinic acetylcholine receptors may suppress male rat sexualbehavior (Soulairac 1963; Bignami 1966; Leavitt 1969)" And from (Hull et al., 1988): "The muscarinic agonist oxotremorine, injected alone into the preoptic area decreased ejaculatory threshold (i.e., decreased the number of intromissions preceding ejaculation) as previously reported. These data suggest that some cholinergic activation of the preoptic area is critical for normal copulation, since bilateral blockade of muscarinic receptors there dramatically decreased the number of animals copulating. However, increased cholinergic activity there only reduced ejaculation threshold."

Now, these studies also find that some stimulation of muscarinic receptors is required for sexual behavior. What is required is the right level.

Yet more evidence:

Some users on this forum have reported cases in which they do not experience POIS symptoms (e.g. sometimes after nocturnal emissions, myself included). This evidence seems hard to square with a theory of POIS as auto-immune condition. In contrast, if overstimulation of muscarinic receptors causes POIS, it is plausible that this overstimulation does not happen for some of us during nocturnal emissions - the vagus nerve (which regulates ACh release and thus stimulation of muscarinic receptors) might "function" better at night for these users.

How the hypothesis could be tested

The hypothesis could be tested in different ways.

First, stimulation of muscarinic receptors could be downregulated by cholinesterase inhibitors. (See https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor for a list)

Second, stimulation of muscarinic receptors could be downregulated by muscarinic antagonists. (See https://en.wikipedia.org/wiki/Muscarinic_antagonist for a list)

Both should make POIS less severe - and could help with premature ejaculation.

IMPORTANT: I DO NOT SUGGEST THAT WE TEST THESE HYPOTHESES BY OURSELVES.

I am looking forward to hearing your thoughts.


REFERENCES:

Giuliano, Fran?ois, and Pierre Cl?ment. ?Anatomy and Physiology of Ejaculation.? In Premature Ejaculation, edited by Emmanuele A. Jannini, Chris G. McMahon, and Marcel D. Waldinger, 25?44. Springer Milan, 2013. http://link.springer.com/chapter/10.1007/978-88-470-2646-9_3.

Gil, L, L. E G?mez, I Dur?n, and R Cueva-Rol?n. ?Muscarinic Mediation of the Urethro Genital Reflex in Spinal Cord-Transected Rats.? Pharmacology Biochemistry and Behavior 67, no. 2 (October 2000): 215?23. doi:10.1016/S0091-3057(00)00323-3.

Ahlenius, Sven, and Knut Larsson. ?Central Muscarinic Receptors and Male Rat Sexual Behavior: Facilitation by Oxotremorine but Not Arecoline or Pilocarpine in Methscopolamine Pretreated Animals.? Psychopharmacology 87, no. 2 (October 1985): 127?29. doi:10.1007/BF00431794.

Hull, Elaine M., Elizabeth A. Pehek, Daniel Bitran, Gregory M. Holmes, Robert K. Warner, Linda C. Band, Terence Bazzett, and Lynwood G. Clemens. ?Brain Localization of Cholinergic Influence on Male Sex Behavior in Rats: Antagonists.? Pharmacology Biochemistry and Behavior 31, no. 1 (September 1988): 175?78. doi:10.1016/0091-3057(88)90330-9.

« Last Edit: January 17, 2016, 03:50:03 PM by BluesBrother »
Used to have brain fog, flue-like symptoms, un-refreshing sleep, extreme exhaustion, muscle and joint pain, digestive problems, social anxiety, urge to urinate frequently.
Used niacin in the past. Now using nanna1's maintenance stack. Exhaustion and brain fog now main problem. 3-day POIS cycle

Marcusq

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #1 on: January 17, 2016, 04:52:29 PM »
Thank you for your report BluesBrother, it seems to have full of sense...

I don't use to have POIS in my nocturnal emissions, and never when I'm with a girl...so I consider POIS a pshycological induced illness

FloppyBanana

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #2 on: January 17, 2016, 05:37:06 PM »
Interesting question!

FYI - glycopyrrolate is an ACH blocker which reduces muscarinic activity. It is often used in conjunction which ACH blockers which have a muscarinic effect. I believe it is called a competitive relationship.

I take muscarinic ACH blockers and what I noticed is that taking it after shooting does not help and can even trigger POIS. This is because I believe sperm production is stimulated. Reason I believe this is because I used to take Mytelase day after sex and when I went to the toilet there was loads of sticky stuff which...triggered POIS:-(

I want to get glycopyrrolate but its not that easy to get so far...
FB
30 years of POIS. Mytelase after O with Iceman breathing technique.

BluesBrother

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #3 on: January 18, 2016, 04:22:25 PM »
I take muscarinic ACH blockers and what I noticed is that taking it after shooting does not help and can even trigger POIS. This is because I believe sperm production is stimulated. Reason I believe this is because I used to take Mytelase day after sex and when I went to the toilet there was loads of sticky stuff which...triggered POIS:-(

As far as I understand, cholinesterase inhibitors can also increase stimulation of receptors (as the concentration of ACh increases). I still do not fully understand the mechanism. Maybe someone else can explain it to me? Here is my current understanding:

If cholinesterase (the breakdown of ACh) is inhibited, the concentration of ACh increases which initially leads to more stimulation of receptors. But eventually, as the concentration of ACh in the synaptic cleft increases, ACh is not released anymore from its receptors, which results in impeded neurotransmission - thus less stimulation (see https://en.wikipedia.org/wiki/Acetylcholinesterase).

You write about muscarinic ACh blockers - do you mean muscarinic antagonists? If yes, I do not immediately see how your experience of symptoms being triggered if taken after ejaculation fits the hypothesis - in my understanding, muscarinic antagonists just block the receptors, thus immediately leading to less stimulation - thus not featuring the initial increased stimulation as would be the case with cholinesterase inhibitors. However, if by 'blockers' you mean cholinesterase inhibitors your observation would fit with the hypothesis:

I hypothesize that overstimulation of muscarinic receptors results in POIS. If now muscarinic receptors have already been overly stimulated during ejaculation and you then take a cholinesterase inhibitor, the receptors are initially even more stimulated - which makes symptoms worse. Stimulation of muscarinic receptors seems to be involved in the secretion of seminal fluid - which you might have seen in your urine. But the symptoms would not have been caused by the seminal fluid, but by the (over)stimulation of muscarinic receptors.

If instead cholinesterase inhibitors are taken before ejaculation (and I suppose sufficient time before), stimulation of receptors also increases initially - but maybe not sufficiently to trigger POIS symptoms (unless one has overdosed on cholinesterase inhibitors) If then there is sufficient ACh 'floating around' there will be less stimulation of muscarinic receptors during ejaculation - which could prevent symptoms.

My understanding of all of these processes is extremely rudimentary, hence it might be that I am completely missing the point.
Used to have brain fog, flue-like symptoms, un-refreshing sleep, extreme exhaustion, muscle and joint pain, digestive problems, social anxiety, urge to urinate frequently.
Used niacin in the past. Now using nanna1's maintenance stack. Exhaustion and brain fog now main problem. 3-day POIS cycle

Quantum

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #4 on: January 18, 2016, 10:48:21 PM »
As far as I understand, cholinesterase inhibitors can also increase stimulation of receptors (as the concentration of ACh increases). I still do not fully understand the mechanism. Maybe someone else can explain it to me? Here is my current understanding:

If cholinesterase (the breakdown of ACh) is inhibited, the concentration of ACh increases which initially leads to more stimulation of receptors. But eventually, as the concentration of ACh in the synaptic cleft increases, ACh is not released anymore from its receptors, which results in impeded neurotransmission - thus less stimulation (see https://en.wikipedia.org/wiki/Acetylcholinesterase).


Hi BluesBrother,

I will try to help you gain a clearer view about the effects of acetylcholinesterase inhibitors ( or AChEI ).  I will try to keep it simple, but there are many parameters to consider.

First part above is correct.  AChEI increase ACh activity by inhibiting the enzyme that metabolizes/breaks ACh, so it becomes more abundant in the synaptic cleft.

However, you have to think that at the molecular level, at the level of receptors and neurotransmitters, it is a very dynamic process.  All this happens in spans of microseconds. When you introduce a drug, what you do as that you "tweek" the rate of one of these steps, in a part of the sites where that happens ( the higher the dose, the more sites - the more synaptic clefts and ACh receptors sites, in our current case -  are affected).   So, in this case, if the introduction of a AChEI slows down the "stop" phase of the ACh action, you will see as a net result a higher Ach/cholinergic effect ( bronchoconstriction, digestive cramps, salivation, and increase in any effect you should expect from cholinergic activity). 

But,  a very important concept is the type of AChEI that is used.  There are reversible AChE inhibitors, and irreversible ones, the difference between the two being the duration of the inhibition on a particular acetylcholinesterase molecule  ( https://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor ).  For reversible one, it is from seconds to minutes, and for so called "irreversible" ones, it is hours to days.   The distinction is very, very important, because the irreversible ones are usually poisons or toxins, like venoms, pesticides or chemical weapons like Sarin ( https://en.wikipedia.org/wiki/Sarin ), and the reversible ones may have therapeutic applications.  In the case of the irreversible ones, they inhibits AChE for so long that ACh can stay active on ACh receptors for extended period of times, and concentration of ACh in the synaptic cleft becomes so high that the result is a constant cholinergic over-stimulation.  In humans, that can lead to death very quickly, as in the case of Sarin, an extremely potent irreversible AChEI, mainly because of the severe bronchospasms  induced by the constant cholinergic stimulation, leading to asphyxia.  For the reversible ones, any acetylcholinesterase molecule can be alternatively on and off. It can be rendered ineffective for a few seconds, than active again when the reversible AChEI let it go, that do some ACh breaking down, than can be blocked again by another AChEI molecule, and so on, in a very rapid and dynamic way.  So, depending on the dose, you more or less taper down the AChE rate of activity by introducing a certain amount of reversible AChEI molecules in the game. 

Mytelase, of course, is a reversible AChEI.

Ok, if you have followed me so far, here is another thing to consider:  the distribution pattern of any particular AChEI, in particular, if it crosses or not the blood brain barrier ( BBB ), so it can pass into the brain.  If you it does not pass the BBB, an AChEI will be good for muscle weakness in the body, but not for cognition and memory problems, because that happens in the brain.  If a particular AChEI is to be effective for brain fog or memory problems, as in Alzheimer disease, it must be able to cross the BBB.  Moreover, you have sub-types of AChE, and, for example, if a AChEI is more specific for the AChE G4 isomeric type, found mainly in the brain, it will have more effect in the brain, and less elsewhere in the body.


For this part you quote from wikipedia: 
"But eventually, as the concentration of ACh in the synaptic cleft increases, ACh is not released anymore from its receptors, which results in impeded neurotransmission - thus less stimulation (see https://en.wikipedia.org/wiki/Acetylcholinesterase).", this affirmation does not fit with what I have learned about ACh activity, and about other neurotransmitters activity as well  ( as a matter of fact, there is no reference to back up this affirmation in the wikipedia article, and a wikipedian has put a "citation needed" at the end. )  What is currently accepted in molecular biology is that when AChE is less active, ACh is more present in the synaptic cleft, and any neurotransmitter that is more present in the synaptic cleft will see its action reinforced. There are more ACh molecules to bind and activate the cholinergic receptors, so the cholinergic effects will step up.  So, I do not agree with the "impeded neurotransmission" and "less stimulation" of the above wikipedia quote.  In clear, if you are using AChE inhibitors, you will strengthen cholinergic activity ( with no "secondary inhibitory phase", to my knowledge and considering what is currently known in molecular biology ).

I hope this will be of help in your understanding of AChEI.

So, BluesBrother, if you think POIS is caused by overstimulation of muscarinic receptors, than AChEI should worsen POIS.  I would add, as a personal view, that those suffering from cognitive problems like brain fog and memory problems show symptoms more akin to a central nervous system cholinergic deficit, rather than a "hypercholinergic" activity.  In fact, I suspect that those who could benefit from AChEI are those who have what I call "Cluster 3" symptoms, that is, mostly, cognitive symptoms, muscular symptoms and dermatological symptoms ( see http://poiscenter.com/forums/index.php?topic=2027.0 for a more complete list of cluster 3, pellagra-like symptoms ).  I do not think an imbalance in ACh would easily explain all other clusters of symptoms, like allergy-like symptoms, flu-like symptoms and emotional symptoms ( but again, this is only my opinion).


As a side note, there are two natural products that have shown to be, among other things, reversible, and rather safe, AChEI inhibitors:  huperzine A, and rosmarinic acid.  However, they have many other properties as well, and the effect you get by taking these is not "pure" AChEI activity.  I personally use rosmarinic acid, but I came to use it because of its IDO inhibitor properties.  I have read of members who had improvement of cognitive functions using huperzine A, which is in line with what can be expected from this supplement ( https://examine.com/supplements/huperzine-a/ ). 

Since I do not have neither memory or cognitive problems, nor muscle weakness, my sub-type of POIS do not seems to be related to a lack of cholinergic activity, at least not as a overall systemic lack.







« Last Edit: January 19, 2016, 12:20:08 AM by Quantum »
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BluesBrother

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #5 on: January 19, 2016, 04:15:05 PM »

Hi BluesBrother,

I will try to help you gain a clearer view about the effects of acetylcholinesterase inhibitors ( or AChEI ).  I will try to keep it simple, but there are many parameters to consider.


Hi Quantum, thank you so much for your clear and helpful explanations. I include some comments and questions below.



Ok, if you have followed me so far, here is another thing to consider:  the distribution pattern of any particular AChEI, in particular, if it crosses or not the blood brain barrier ( BBB ), so it can pass into the brain.  If you it does not pass the BBB, an AChEI will be good for muscle weakness in the body, but not for cognition and memory problems, because that happens in the brain.  If a particular AChEI is to be effective for brain fog or memory problems, as in Alzheimer disease, it must be able to cross the BBB.  Moreover, you have sub-types of AChE, and, for example, if a AChEI is more specific for the AChE G4 isomeric type, found mainly in the brain, it will have more effect in the brain, and less elsewhere in the body.


I hypothesized that POIS might be due to overstimulation of muscarinic receptors - the symptoms I have in mind are physical, rather than cognitive. I should have been clearer about that. As I understand, for cognitive function nicotinic receptors are more important than muscarinic receptors. It might well be that stimulation of nicotinic receptors could help with cognitive POIS symptoms. In contrast, as far as I understand muscarinic receptors play a larger role than nicotinic receptors in ejaculation. The symptoms of overstimulation of muscarinic receptors seem to resemble part of the physical POIS symptoms.


For this part you quote from wikipedia: 
"But eventually, as the concentration of ACh in the synaptic cleft increases, ACh is not released anymore from its receptors, which results in impeded neurotransmission - thus less stimulation (see https://en.wikipedia.org/wiki/Acetylcholinesterase).", this affirmation does not fit with what I have learned about ACh activity, and about other neurotransmitters activity as well  ( as a matter of fact, there is no reference to back up this affirmation in the wikipedia article, and a wikipedian has put a "citation needed" at the end. )  What is currently accepted in molecular biology is that when AChE is less active, ACh is more present in the synaptic cleft, and any neurotransmitter that is more present in the synaptic cleft will see its action reinforced. There are more ACh molecules to bind and activate the cholinergic receptors, so the cholinergic effects will step up.  So, I do not agree with the "impeded neurotransmission" and "less stimulation" of the above wikipedia quote.  In clear, if you are using AChE inhibitors, you will strengthen cholinergic activity ( with no "secondary inhibitory phase", to my knowledge and considering what is currently known in molecular biology ).


I tried to find out where the statement on Wikipedia might have its origin. I found this article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648782/
I quote: "The inhibition of the enzyme leads to accumulation of ACh in the synaptic cleft resulting in over-stimulation of nicotinic and muscarinic ACh receptors and impeded neurotransmission."

This clarifies the confusion. You are right that AChEI leads to more stimulation of ACh receptors. What is lowered is the transmission of new signals, not the stimulation of receptors. Here is where I went wrong previously.


So, BluesBrother, if you think POIS is caused by overstimulation of muscarinic receptors, than AChEI should worsen POIS.  I would add, as a personal view, that those suffering from cognitive problems like brain fog and memory problems show symptoms more akin to a central nervous system cholinergic deficit, rather than a "hypercholinergic" activity.  In fact, I suspect that those who could benefit from AChEI are those who have what I call "Cluster 3" symptoms, that is, mostly, cognitive symptoms, muscular symptoms and dermatological symptoms ( see http://poiscenter.com/forums/index.php?topic=2027.0 for a more complete list of cluster 3, pellagra-like symptoms ).


As I wrote above, I considered overstimulation of muscarinic receptors during ejaculation a potential explanation for some part of the physical POIS symptoms. I agree that when it comes to cognitive symptoms, under- rather than overstimulation of (nicotinic) receptors seems more plausible. I also agree that in principle AChEI should then worsen the physical POIS symptoms. Unless the increased stimulation of muscarinic receptors as a result of AChEI before ejaculation desensitizes the receptors for stimulation during ejaculation. I have no idea whether that would be at all plausible. What do you think? Desensitization of muscarinic receptors due to AChE deficiency has been observed in mice (see http://onlinelibrary.wiley.com/doi/10.1002/ana.10589/full) - however, as I understand, desensitization occured there over a longer period.


I do not think an imbalance in ACh would easily explain all other clusters of symptoms, like allergy-like symptoms, flu-like symptoms and emotional symptoms ( but again, this is only my opinion).


Many of the symptoms associated with POIS also seem to occur after overstimulation of muscarinic receptors, inlcuding

allergy-like symptoms: Lacrimation, Rhinorrhea, Bronchorrhea (see http://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=9)
flu-like symptoms: sweating
Cluster 3 peripheral symptoms:Diarrhea, Abdominal cramps

So far I have mostly focused on overstimulation of muscarinic receptors. But it seems that also overstimulation of nicotinic receptors leads to symptoms which occur in POIS:

"Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma." (https://en.wikipedia.org/wiki/Organophosphate_poisoning#Signs_and_symptoms)

Hence also emotional symptoms could be rooted in ACh being out of balance (although rather via nicotinic receptor overstimulation). Also the findings by Prof. Komisaruk of POIS symptoms being accompanied by a lower heart rate could point towards higher ACh. However, I also think that POIS is probably more complex than can be explained by ACh "imbalance".

To summarize: to me it still seems as if imbalances in ACh (overstimulation of muscarinic and nicotinic receptors) could play a role in POIS - few other hypothesized channels seem to generate such a large intersection with POIS symptoms. But maybe I am missing something?

What does not anymore fit the hypothesis though, is that cholinesterase inhibitors have helped users Outsider and FloppyBanana eliminate POIS symptoms. Unless desensitization of receptors could be a factor. I'd be very curious to hear your thoughts on this.

As a side note, there are two natural products that have shown to be, among other things, reversible, and rather safe, AChEI inhibitors:  huperzine A, and rosmarinic acid.  However, they have many other properties as well, and the effect you get by taking these is not "pure" AChEI activity.  I personally use rosmarinic acid, but I came to use it because of its IDO inhibitor properties.  I have read of members who had improvement of cognitive functions using huperzine A, which is in line with what can be expected from this supplement ( https://examine.com/supplements/huperzine-a/ ). 

Thanks, I had also come across those.
Used to have brain fog, flue-like symptoms, un-refreshing sleep, extreme exhaustion, muscle and joint pain, digestive problems, social anxiety, urge to urinate frequently.
Used niacin in the past. Now using nanna1's maintenance stack. Exhaustion and brain fog now main problem. 3-day POIS cycle

b_jim

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #6 on: January 19, 2016, 04:32:22 PM »
Yes, yes !
I wrote something about muscarinic receptors, acethylcholine, botulism...
But I don't find it :]

The symptoms of botulism are interesting :
- muscles weakness
- double vision
- words confusion
-lightheadedness

Cholin deficiency is very possible :
Quote
The choline researcher Dr. Steven Zeisel wrote: "A recent analysis of data from NHANES 2003–2004 revealed that for [American] older children, men, women and pregnant women, mean choline intakes are far below the AI. Ten percent or fewer had usual choline intakes at or above the AI."

One ejaculation may contain 5 to 8 mg of cholin. And Taurine may improve cholin absorbtion.

« Last Edit: January 19, 2016, 04:51:44 PM by b_jim »
Taurine + Choline = Anti-Pois
Lyme disease "cured" in 2020.

Quantum

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #7 on: January 19, 2016, 11:30:48 PM »
Interesting question!

FYI - glycopyrrolate is an ACH blocker which reduces muscarinic activity. It is often used in conjunction which ACH blockers which have a muscarinic effect. I believe it is called a competitive relationship.

I take muscarinic ACH blockers and what I noticed is that taking it after shooting does not help and can even trigger POIS. This is because I believe sperm production is stimulated. Reason I believe this is because I used to take Mytelase day after sex and when I went to the toilet there was loads of sticky stuff which...triggered POIS:-(

I want to get glycopyrrolate but its not that easy to get so far...
FB

Hi FB,

I am not sure if I understand it well, but did you stop to use Mytelase ?  Effectiveness against your POIS did not last ?
You are 100% responsible for what you do with anything I post on this forum and of any consequence it could have for you.  Forum rule: ""Do not use POISCenter as a substitute for, or to give, medical advice" Read the remaining part at http://poiscenter.com/forums/index.php?topic=1.msg10259#msg10259

Quantum

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #8 on: January 19, 2016, 11:42:18 PM »

Hi Quantum, thank you so much for your clear and helpful explanations. I include some comments and questions below.

Hi BluesBrother,

I will try to come back to your other questions when I will have the time to do so.  For now, there is a few notes that came to mind when reading your message.

First, I wanted to let you know that there are nicotinic receptors as well at the neuromuscular junctions ( not only muscarinic) https://en.wikipedia.org/wiki/Muscle-type_nicotinic_receptor


Another note that came to mind, and I have checked about this:  Mytelase is an excellent AchEI, but do not cross the BBB ( http://www.sciencedirect.com/science/article/pii/S0014827X03001502 ).  Then, it  may be of help in POIS, as it can help with muscle weakness, and doing so without aggravating cognitive symptoms, as it do not make it into the brain ( However, the last comment of FB makes me wonder if he still has good results with Mytelase, or not - see my previous message, hoping to get more information from him).  I would also like to know from Outsider, and FB too,  what symptoms went away with Mytelase, exactly.  I read Outsider's posts, and he began lecithine, as a choline source, at the same time as Mytelase, which makes me thinks that if he has central nervous system relief, the lecithin would be the source of this relief, and not the Mytelase, which do not cross the BBB, and if it would, it would likely worsen cognitive symptoms.
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BluesBrother

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #9 on: January 20, 2016, 04:45:01 PM »

Hi Quantum, thank you so much for your clear and helpful explanations. I include some comments and questions below.

Hi BluesBrother,

I will try to come back to your other questions when I will have the time to do so.  For now, there is a few notes that came to mind when reading your message.

First, I wanted to let you know that there are nicotinic receptors as well at the neuromuscular junctions ( not only muscarinic) https://en.wikipedia.org/wiki/Muscle-type_nicotinic_receptor


Thanks for pointing that out. I had focused my discussion above on muscarinic receptors as those seem to be more important in sexual responses. I found this to be an interesting and easy to read review:

Floody, Owen R. ?Role of Acetylcholine in Control of Sexual Behavior of Male and Female Mammals.? Pharmacology Biochemistry and Behavior 120 (May 2014): 50?56. doi:10.1016/j.pbb.2014.02.007. http://www.sciencedirect.com/science/article/pii/S0091305714000380

As most studies in this area (from what I have seen), it focuses on the effect of cholinergic agonists and antagonists on sexual behavior in animals - and one might question to what extent the findings are transferrable to humans, especially since there are already large differences across animals. That aside, here are the "highlights":

- Reviews studies of cholinergic influences on male and female sexual behaviors
- These support strong cholinergic influences on both behaviors.
- At least in males, these effects differ across behaviors and species.
- In both sexes, most effects originate centrally and are muscarinic.
- But few can be attributed to a specific brain area or receptor subtype.


Still, there seems to be some role for nicotinic receptors in sexual responses - for example erectile function is discussed. After having read the list of symptoms resulting from overstimulation of nicotinic receptors, those might also play a role in POIS. We discussed above whether the symptoms of over- or understimulation of (in that case nicotinic) receptors are more in line with POIS symptoms. It might be both (or at least the neurotransmission involving nicotinic receptors might be lowered):

Excerpt from http://www.dartmouth.edu/~rpsmith/Cholinergic_Transmission.htm

Cholinergic Transmission

At the nicotinic receptors in ganglia and at the myoneural junction the accumulation of acetylcholine at first leads to an intensification of cholinergic transmission, but with continued accumulation over time, the nicotinic receptors become desensitized. There follows a failure of nicotinic, cholinergic transmission, despite the continued presence of excess transmitter. This results in flaccid paralysis of skeletal muscle and a fall off of sympathetic autonomic function. Parasympathetic autonomic function, however, remains intensified even though the parasympathetic ganglia may have been desensitized.


It could thus be that during ejaculation (or potentially already during secretion of seminal fluid) both, muscarinic and nicotinic receptors are overstimulated, leading to symptoms such as diarrhea, sweating, allergy and flu-like symptoms (due to overstimulation of muscarinic receptors) as well as anxiety, depression (due to overstimulation of nicotinic receptors). As then nicotinic receptors become desensitized, the impeded neurotransmission could relate to cognitive symptoms.

I know that this is a lot of speculation - still, I wanted to put it up for discussion.

Another note that came to mind, and I have checked about this:  Mytelase is an excellent AchEI, but do not cross the BBB ( http://www.sciencedirect.com/science/article/pii/S0014827X03001502 ).  Then, it  may be of help in POIS, as it can help with muscle weakness, and doing so without aggravating cognitive symptoms, as it do not make it into the brain ( However, the last comment of FB makes me wonder if he still has good results with Mytelase, or not - see my previous message, hoping to get more information from him).  I would also like to know from Outsider, and FB too,  what symptoms went away with Mytelase, exactly.  I read Outsider's posts, and he began lecithine, as a choline source, at the same time as Mytelase, which makes me thinks that if he has central nervous system relief, the lecithin would be the source of this relief, and not the Mytelase, which do not cross the BBB, and if it would, it would likely worsen cognitive symptoms.

I agree, it would be very important to know more about the experiences of Outsider and FB.

FB wrote:

It's worth noting Mytelase will only work for me if I take it before having O. I have to take in morning, lunch then dinner...then shoot. So shooting requires planning nearly a day ahead.

Maybe some sort of desensitization of receptors is indeed involved. In that same thread you also discussed the role of caffeine and hot showers - which make symptoms worse. This does not quite fit within my theory:

Caffeine seems to inhibit cholinesterase (see e.g. Pohanka, Miroslav, and Petr Dobes. ?Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase.? International Journal of Molecular Sciences 14, no. 5 (May 8, 2013): 9873?82. doi:10.3390/ijms14059873. http://www.mdpi.com/1422-0067/14/5/9873/htm )

According to my hypothesis, it should make symptoms worse when taken after orgasm - but might prevent symptoms if taken before orgasm. In contrast, you wrote

It sounds like there may be an "Acetylcholine subtype" of POIS.  It could be identified by the fact that a hot shower makes the POIS symptoms more severe, and a cold shower brings relief  ( see https://en.wikipedia.org/wiki/Myasthenia_gravis#Ice_test , where it is explained that the acetylcholinesterase activity decreases at lower temperature ).  Caffeine could also be detrimental to those POIS sufferers, but that would have to be confirmed, though.

Hot showers should thus stimulate cholinesterase, thus leading to lower ACh - the opposite effect of that of caffeine. (Btw. in my case caffeine seems to make symptoms worse when in POIS - I have not noted any effect of hot showers)

Finally, I completely agree with what you wrote in that other thread: There might be an "Acetylcholine subtype" of POIS. Like you, I am certain that there is no one type of POIS - symptoms cluster in quite different ways across people. My hypothesis might apply only to the "ACh-type" of POIS.
Used to have brain fog, flue-like symptoms, un-refreshing sleep, extreme exhaustion, muscle and joint pain, digestive problems, social anxiety, urge to urinate frequently.
Used niacin in the past. Now using nanna1's maintenance stack. Exhaustion and brain fog now main problem. 3-day POIS cycle

VSmasher

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #10 on: January 21, 2016, 09:29:04 PM »
Nutmeg is a Muscarinic Acetycholine receptor antagonist. Do you think it would work?
My POIS Symptoms:  Brain Fog, frustration, stuffed nose, anger, anxiety, intense hunger, low self esteem, swollen face, and feel zoned out.

b_jim

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #11 on: January 22, 2016, 04:57:52 PM »
Nutmeg is a Muscarinic Acetycholine receptor antagonist. Do you think it would work?

I think some guys said nutmeg improves symptoms.
Taurine + Choline = Anti-Pois
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demografx

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #12 on: January 22, 2016, 06:38:46 PM »
"A Warning on Nutmeg"
New York Times, November 25, 2014
http://mobile.nytimes.com/blogs/well/2014/11/25/a-warning-on-nutmeg/?referer=
10 years of significant POIS-reduction, treatment consisting of daily (365 days/year) testosterone patches.

TRT must be checked out carefully with your doctor due to fertility, cardiac and other risks.

40+ years of severe 4-days-POIS, married, raised a family, started/ran a business

BluesBrother

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #13 on: January 24, 2016, 06:07:19 PM »
"A Warning on Nutmeg"
New York Times, November 25, 2014
http://mobile.nytimes.com/blogs/well/2014/11/25/a-warning-on-nutmeg/?referer=

Thanks demo for highlighting the dangers of nutmeg.

Nutmeg is a Muscarinic Acetycholine receptor antagonist. Do you think it would work?

I have no idea - I have just been hypothesizing about the role of muscarinic receptors. Please do not try any treatments without consulting your GP. I also want to highlight that I have no medical expertise - I am just collecting information for further discussion and investigation.
Used to have brain fog, flue-like symptoms, un-refreshing sleep, extreme exhaustion, muscle and joint pain, digestive problems, social anxiety, urge to urinate frequently.
Used niacin in the past. Now using nanna1's maintenance stack. Exhaustion and brain fog now main problem. 3-day POIS cycle

demografx

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #14 on: January 31, 2016, 03:41:54 PM »

Please do not try any treatments without consulting your GP.
Thanks, BluesBrother
That statement is worth repeating!
10 years of significant POIS-reduction, treatment consisting of daily (365 days/year) testosterone patches.

TRT must be checked out carefully with your doctor due to fertility, cardiac and other risks.

40+ years of severe 4-days-POIS, married, raised a family, started/ran a business

Nas

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #15 on: March 23, 2016, 10:41:48 PM »
So, what about psychological symptoms of POIS do you think it's vagus nerve related ? and how to fix it if so ?

bunyip

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #16 on: September 06, 2021, 02:01:12 AM »

Gil et al. (2000) write "also, it has been suggested that acetylcholine may play a role in the phenomenon of premature ejaculation [2]." They quote Ahlenius and Larsson (1985) who write "It is possible, however, that the antimuscarinic effects
of thioridazine and chlofimipramine are responsible for the effects of these drugs on time to ejaculation. "

The phenothiazine thioridazine/mellaril caused my POIS.

The inability to ejaculate kicks in within 6 hours is the first noticeable side effect of this dangerous drug (now withdrawn from the market due to association with sudden death syndrome ('Torsades de pointes' --> https://en.wikipedia.org/wiki/Torsades_de_pointes).


Progecitor

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #17 on: September 06, 2021, 12:00:36 PM »

Gil et al. (2000) write "also, it has been suggested that acetylcholine may play a role in the phenomenon of premature ejaculation [2]." They quote Ahlenius and Larsson (1985) who write "It is possible, however, that the antimuscarinic effects
of thioridazine and chlofimipramine are responsible for the effects of these drugs on time to ejaculation. "

The phenothiazine thioridazine/mellaril caused my POIS.

The inability to ejaculate kicks in within 6 hours is the first noticeable side effect of this dangerous drug (now withdrawn from the market due to association with sudden death syndrome ('Torsades de pointes' --> https://en.wikipedia.org/wiki/Torsades_de_pointes).



Could you go into a bit more detail? Why are you certain it was thioridazine? How long have you taken the drug? Have you noticed POIS while you took the drug or only after you stopped using it. What are your major symptoms? Have you found any supplements or methods that can reduce your symptoms?

Cursed

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #18 on: September 08, 2021, 07:31:53 AM »
I think this is a very good hypothesis! I can't digest everything because of severe brain fog, but I can tell from personal experience that my POIS symptoms, erection quality, PE all depend highly on the gut and stimulation/irritation of the gut, which is of course connected to the vagus nerve and maybe the gut bacteria/gut permeability could be the cause of this blockade or sensitization of the receptors.


Adding: in fact, I have nearly constant runny/stuffed nose, have lower heart rate than I should have at rest, and I have had a few episodes of bradycardia when I had overdone it on fat. So there you have it.
« Last Edit: September 08, 2021, 07:36:51 AM by Cursed »

FernandoPOIS

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Re: Does POIS result from overstimulation of muscarinic receptors
« Reply #19 on: September 09, 2021, 08:50:46 AM »
This entire process that we go through is due to excess vasodilation caused by stress that causes low serotonin, sedentary lifestyle that causes low dopamine and endorphins and muscle weakness (genetic) that makes us more susceptible to pain and tension. As long as this cycle is not broken, studying receptors and drugs wont help.
My POIS only happens with masturbation. Normal sex does not generate POIS symptoms. When I have no back pain and I masturbate the POIS symptoms are weaker and last for at most 2 days. My POIS is related to the health of my thoracic and cervical spine. Postural and Aerobic Exercise heal the vagus.