The role of norepinephrine/noradrenaline

[Progecitor]

My personal thoughts and experiences so far

Catecholamine depletion has been already discussed as a possible cause of POIS. My recent experiences also seem to comply. However the cause and effect relationship is not necessarily straightforward. Bloodshot eyes tend to emerge most rapidly and robustly about an hour after ejaculation, though the issue can be present even before that. The ocular hyperemia is caused by vasodilation and this may indicate an insufficiency in norepinephrine (NE) activity. Interestingly NE has an immunosuppressive and anti-inflammatory effect as well, by reducing the production of pro-inflammatory cytokines. This places NE besides estrogen receptor beta and sigma-1 agonists that have a similar function. It is worth mentioning that acetylcholine also seems to have a similar role. Interestingly all four of these upregulate BDNF as well, which has a controversial role in immunosupression. Nevertheless NE appears to be particularly effective as an anti-depressant. A new study also shows that NE has a crucial role in removing waste from the brain during sleep and this could inhibit neurodegeneration.

On a recent trial, I have found naphazoline eye drops to have a very significant benefit. Only 1 drop in each eye reduced bloodshot eyes one degree and afterwards it had such a prolonged anti-depressive effect, that I couldn’t even sleep. It was quite amazing really! Of course it will probably not work so well on the long run, but it surely indicates a positive role for norepinephrine/noradrenaline.
I have to note that on this day I also took bupropion in the morning and one capsule of yohimbine about 4 hours before applying the naphazoline drops. This may have resulted in some synergism.
Even more recently I found a combined yohimbine/rauwolscine supplement to have a marked positive effect on my POIS symptoms as well. I also had a positive experience with venlafaxine in the past, though bupropion does not seem to do anything individually even after 4 months of continuous taking. I also tried phenylephrine nasal drops that can help with nasal congestion, but besides that it was practically useless against POIS symptoms. Interestingly I also found butcher’s broom to be a little useful, though I can’t say it did particularly much when I was taking it continuously.

Quotes from other members involving the benefits of norepinephrine

There is indication that a combination of norepinephrine boosters and sigma-1 agonists could be useful.

https://www.reddit.com/r/POIS/comments/zrs9qo/related_to_allergic_rhinitis_nasal_drops/
"I took Refenax nasal drops (which have Diphenhydramine hydrochloride, and Naphazoline hydrochloride) and started to feel better from POIS."

Over-the-Counter Ocular Decongestants in the United States – Mechanisms of Action and Clinical Utility for Management of Ocular Redness
Nasal congestion
Red eyes
Naphazoline eye drops for neurosomatic disorders/neural network disorders are being used but higher concentration like 0.1%, 1 drop in each eye.

Milnacipran could be really useful, but unfortunately it has not been introduced in our country yet.

I've been suffering from POIS since 2000, posting on POIS forums since 2009 (Naked Scientist Forum) and more recently on here (since 2011), and I've finally found something that has consistently worked for me.

For the last 6 weeks, I've been taking milnacipran (Savella) before O. After O, there has been no brain fog - every time. My physical symptoms (dry hair, dry forehead, clicking knees) have also gone.

The milnacipran has an unusual side-effect - my Os feel much more intense, and last much longer. This hasn't happened with any other medicines I have tried, and I have tested many different medicines over the years. Again, this happens every time.

I have been taking one dose of 25mg approximately 1 to 1.5 hours before O. Initially I combined it with fenugreek, but now I take it on its own. The result has been 0% brain fog every time.

Milnacipran is an SNRI that inhibits norepinephrine reuptake even at low doses - other popular SNRIs venlafaxine and duloxetine (which I have tried) need much higher doses before there is any significant inhibition of norepinephrine reuptake. I believe that it is the norepinephrine action of milnacipran which is somehow preventing my post-O brain fog.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938282/

It is early days now, but I sincerely hope that milnacipran will continue to work for me in the long-term. If it becomes less effective or stops working, I will come back to this thread and update it.

I would be happy to answer any questions.

CFS members also benefit from milnacipran.

The most effective drug I've ever taken is Nortriptyline, so I'm really sorry that I can't take it. The next most effective drug is milnacipran.
https://www.reddit.com/r/cfs/comments/1hzo3rv/norepinephrine_enhances_all_my_brain_functions/

POIS members also benefit from nortriptyline.

Hello. I have a pois for 5 years. I tried many herbal and chemical drugs. My pois is treated by eating honey+5mg nortriptyline!!!

I've recently taken Nortriptyline which reduce my symptoms and recovery days from 7 days to three days but it stopped working after 5 months although i increased the dosage. And then i decided to cut out antidepressants gradually because i think my memory is not as sharp as the past but now i consume low dosage of Nortriptyline my nocturnal emission start to increase. My symptoms take 7 days to fade if i masturbate and 3 days if i have a wet dream.

Prostatitis may be also treated with norepinephrine:

I'm on an anti-depressant called effexor (venlafaxine). Currently its helping my mood, BUT it also treats neuropathic pain because it has a 3:1 affinity for Norepinephrine over serotonin in the brain. This means it will make norepinephrine more available in the brain, and this can actually act as a nerve pain block. Some kid on an online forum said his urethral pain/uncomfortable urine feeling went away in a month on the antidepressant.
https://www.reddit.com/r/Prostatitis/comments/8dnn2d/is_there_an_way_out_except_suicide/

If this is so then ejaculation can certainly lower NE.
The old link is dead. Use this instead:
https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1439-0272.2001.00461.x

High concentration of catecholamines is present in sperm :

http://www.blackwell-synergy.com/doi/abs/10.1046/j.1439-0272.2001.00461.x

"In conclusion, noradrenaline and DOPA are present in human semen at concentrations that are much higher than maximal normal values in plasma."

Noradrenaline : 19 times more than concentration in plasma
Dopa : 2 times

This thread could be potentially be a deeper investigation to Catecholamines deficiency theory. 

I'll start the first topic with this article:  Are you suffering from The Blahs?

This article is well written and articulates many observable phenomena that have been discovered in this forum.

"Dopamine, Epinephrine (adrenaline) and Norepinephrine (noradrenaline) are the primary catecholamines or ‘cats’, as they are known. Catecholamines function both as hormones and neurotransmitters."

"If you have adequate cats, you feel energized, upbeat, alert and focused and you don’t crave caffeine or sugar for a pick-me-up.
If your cats are low, you may feel the kind of depression that lands you curled up in the bed all day with extremely low motivation."
If you ask me I have strong cravings for coffee and sugar when I'm in POIS which could be an indication of low dopamine, it can also explain what it actually helps with POIS.

Many POISers benefit from cold showers and this could be one of the reasons.

thanks hurray , i will give it a try .
My pois symptoms get reduced by cold showers , and i read in some google search that the  ‘Cold Shocking the Body’  increase the release of norepinephrine , and some norepinephrine deficiency cognitive symptoms are the same symptoms of  pois .
 so i suspect that  my pois  was due to a lack of norepinephrine .

Research quotes to show how NE may affect POIS:
See in the attached document!

[Aladin]

Maybe add a word document as an attachment if you want to be complete ?

[Progecitor]

Maybe add a word document as an attachment if you want to be complete ?

Thanks for the suggestion! I did so!

[demografx]

Research quotes to show how NE may affect POIS

Presynaptic neuronal alpha2- and beta-adrenergic receptors function as autoreceptors; stimulation of these receptors decreases norepinephrine release from neuron terminals, which may also contribute to vasodilation.
Ocular redness results from vasodilation of conjunctival blood vessels. In vascular smooth muscle cells, stimulation of a1- and/or a2-adrenergic receptors leads to vasoconstriction, whereas stimulation of beta-adrenergic receptors leads to vasodilation. In addition, stimulation of a1-, a2-, and/or B-adrenergic receptors on vascular endothelial cells leads to vasodilation via a process possibly mediated by increased nitric oxide release.
Naphazoline hydrochloride, another imidazole derivative, is a mixed a1/a2 receptor agonist with a binding affinity of ~2:1 for a2:a1 receptors.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7399465/

Norepinephrine (NE) has been shown to modulate immune cell responses leading to increased anti-inflammatory and blunting of pro-inflammatory effects. Endotoxin exposure led to increased levels of circulating NE, suggesting enhanced sympathetic nerve activity.
In human leukocytes, beta?ADRs (adrenergic receptors) are expressed on natural killer (NK) cells, monocytes, B cells, CD8+ T cells, and CD4+ T cells. NE has been demonstrated to have an overall anti-inflammatory effect, mediated primarily through beta?ADRs.
In-vitro studies have shown many anti-inflammatory immunologic effects, including decreased pro-inflammatory tumor necrosis factor alpha (TNF-alpha), Interleukin (IL)-6, and IL-8, and stimulation of anti-inflammatory cytokine IL-10. The norepinephrine-induced stimulation of IL-10, in addition to attenuation of TNF-alpha and IL-6, have been shown to be diminished by beta-blockade with medications such as metoprolol and propranolol.
As part of the neuroinflammatory reflex, vagal nerve stimulation induces NE release from the spleen, resulting in acetylcholine secretion by CD4+ T-cells. In animal models, stimulation of the vagal nerve attenuates systemic inflammation. Norepinephrine, as well as epinephrine, was found to exert immunosuppressive effects in LPS-stimulated human whole blood, as well as isolated monocytes in vitro.
In humans, ROS deficiency leads to recurrent and severe bacterial infections, whereas uncontrolled release results in excessive inflammation. Upon activation of surface receptors, host immune cells release substantial amounts of ROS at infection sites. There is an abundance of evidence that points to excess ROS contributing to the maladaptive responses in inflammatory states leading to metabolic and global dysfunction. The most common consequences of sepsis are impaired vascular permeability, cardiac malfunction, and mitochondrial dysfunction leading to impaired metabolism and, if left unchecked, shock.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1271098/full

In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-gamma–induced protein. Norepinephrine attenuated the LPS-induced increase in lactate production, indicating inhibition of the glycolytic shift.
Norepinephrine infusion dose-dependently attenuated basal neutrophilic ROS production in LPS-challenged mice and suppressed the maximal neutrophilic respiratory burst in non–LPS-challenged mice.
Our data reveal that the norepinephrine infusion rate is associated with lower plasma TNF-a/IL-10 ratios, indicating a shift toward a more antiinflammatory phenotype, and use of B-blockers was associated with an increased plasma TNF-a/IL-10 ratio, signifying a more proinflammatory phenotype.
https://www.atsjournals.org/doi/full/10.1164/rccm.202002-0339OC

Danish scientists found that a molecule called norepinephrine plays a key role in the brain's cleaning in mice. During deep sleep, the brainstem releases tiny waves of norepinephrine about once every 50 seconds. Norepinephrine triggers blood vessels to contract, generating slow pulsations that create a rhythmic flow in the surrounding fluid to carry waste away. They found that norepinephrine waves correlate to variations in brain blood volume, suggesting norepinephrine triggers a rhythmic pulsation in the blood vessels. The team then compared the changes in blood volume to brain fluid flow. They found that the brain fluid flow fluctuates in correspondence to blood volume changes, suggesting that the vessels act as pumps to propel the surrounding brain fluid to flush out waste.
Their findings may offer insights into how poor sleep may contribute to neurological disorders like Alzheimer's disease.
https://www.sciencedaily.com/releases/2025/01/250108143735.htm
https://www.cell.com/cell/abstract/S0092-8674(24)01343-6

Rapid eye movement latency (REML) may be a potential marker for Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) pathogenesis. Prolonged REML was associated with higher amyloid beta (Abeta) burden, phosphorylated tau-181 (p-tau181), and lower brain-derived neurotrophic factor (BDNF) levels. Growing evidence suggests an association of sleep duration, sleep quality, or excessive daytime sleepiness with amyloid beta (Abeta) deposition assessed by positron emission tomography (PET) scans or cerebrospinal fluid (CSF) measures in older adults. Experimental paradigms of chronic sleep deprivation also led to a substantial increase in interstitial fluid and CSF tau as well as tau pathology spreading in rodent models.
We found a link between longer REML and lower levels of BDNF, an increasingly recognized diagnostic marker and therapeutic target for AD. Research suggests that the impact of BDNF on sleep is more profound for REM sleep, particularly REM sleep drive, which may subsequently aid in the quick onset of REM sleep.
https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.14495

This also outlines a possible way how sexual activity in conjunction with oxidative stress can lead to a fall of norepinephrine level.

Recently, we reported that ONOO?1 oxidized norepinephrine and consequently inactivated its vasoconstrictive actions. ONOO?1 also reacts with dopamine to form an oxidized derivative, 6-hydroxyindole-5-one. If the activity of dopamine treated with ONOO?1 decreases, this may account for dopamine’s limitation as a vasoconstrictor in septic shock.
https://journals.lww.com/anesthesia-analgesia/fulltext/2003/11000/peroxynitrite_decreases_dopamine_s.48.aspx

NE dose-dependently reduced NOS2 expression and NO generation, via activation of B2-adrenergic receptors (B2-ARs), and reduced loss of inhibitory IkBa protein. NE reduces microglial NOS2 expression and IL-1B production, however IL-1B does not play a critical role in NOS2 induction nor in mediating NE suppressive effects.
Microglial activation including the production of pro-inflammatory cytokines and reactive oxygen species is now recognized as a key component of several neurological diseases including Multiple Sclerosis (MS) and Alzheimer's Disease (AD); as well as other conditions in which trauma, infection, or injury leads to inflammatory activation. Activated microglia produce the free radical NO synthesized by the inducible form of the enzyme nitric oxide synthase (iNOS or NOS2).
Depletion of NE exacerbates the cortical inflammatory response to amyloid beta (Abeta). Perturbation in NE levels, or dysfunction in NE signaling might therefore exacerbate inflammatory responses.
We showed that central NE depletion led to a dramatic decrease in cortical levels of the IkBa protein, consistent with the idea that NE normally keeps the IkBa gene transcriptionally active.
https://link.springer.com/article/10.1186/1742-2094-1-9

IkBa (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; NFKBIA) is one member of a family of cellular proteins that function to inhibit the NF-kB transcription factor.
https://en.wikipedia.org/wiki/I%CE%BAB%CE%B1

Take note that 5-HT2C receptors have a role in premature ejaculation, prolactin release, SSRI caused sexual dysfunction and appetite as well. (more on this later)

Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo.
Activation of 5-HT1A receptors facilitates the frontocortical release of both dopamine (DA) and noradrenaline (NA).
https://www.sciencedirect.com/science/article/abs/pii/S0028390898000781

Generally, a1- and B-ARs have a stimulatory effect on cell signaling, as they have been shown to increase intracellular phospholipase C or cyclic adenosine monophosphate (cAMP), respectively, whereas a2-ARs suppress intracellular cAMP and generally have an inhibitory influence on signaling. NE has the highest affinity for a2-ARs so low-level NE release may inhibit neuronal activity, whereas increased neural transmission arising from NE binding to stimulatory a1- and B-ARs only occurs at higher NE concentrations.
NE receptors within these pathways play a role in a broad range of brain functions, such as arousal, stress response, memory consolidation, immune response, endocrine function, sleep/wakefulness, and pain-threshold regulation.
Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), the major NE metabolite, in the cerebrospinal fluid (CSF) have been shown to positively correlate with lifetime mood burden.
Blocking a2-ARs using yohimbine has been shown to improve memory consolidation in patients with major depressive disorder (MDD).
Elevated NE may be associated with cognitive disorganization, poor impulse control, suspiciousness, hostility, and hallucinations. High concentrations of NE have also been shown to reduce working memory function through actions at a1-ARs.
Biochemical studies point to an association between elevated NE levels and decreased sleep efficiency.
It has been shown that antagonism of the DA D2 receptor has both an effect on eating, mediated by 5-HT2C receptors, and disinhibition of prolactin secretion, which has an impact on lipid and glucose metabolism.
Intriguingly, a recent study reported a preferential response to an SSRI (escitalopram) in patients with lower levels of an inflammatory marker [C-reactive protein (CRP) <1 mg/mL], compared with depressed patients with higher inflammation (CRP > 3 mg/mL) who had a robust response to a predominantly noradrenergic antidepressant treatment (nortriptyline).
https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2017.00042/full

Parasympathetic outflow inhibits macrophage activation and subsequent release of pro-inflammatory cytokines such as IL-6 via a nicotinic alpha-bungarotoxin-sensitive macrophage acetylcholine receptor. Electrical stimulation of the vagus nerve inhibits release of pro-inflammatory cytokines in vivo. Increased heart rate variability (HRV) was associated with decreased inflammation. The sympathetic nervous system (SNS) mediates both pro- and anti-inflammatory responses. For example, postganglionic NE has anti-inflammatory effects via adrenoreceptors present on lymphocytes and macrophages. NE, acting non-synaptically, serves as a hormone that inhibits the production of pro-inflammatory cytokines via a beta2-adrenoreceptor-cAMP-protein kinase A pathway. NE stimulation of alpha2-adrenoreceptors is associated with pro-inflammatory effects. Acetylcholine effectively and in a dose-dependent manner suppressed pro-inflammatory cytokines. Extrinsic stimulation of the vagus nerve inhibited the release of pro-inflammatory cytokines and prevented inflammation.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2008.02023.x

Acute vagus nerve stimulation (VNS) increased the expression of brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (bFGF) in the hippocampus and cerebral cortex, decreased the abundance of nerve growth factor (NGF) mRNA in the hippocampus, and, similar to the antidepressant drug venlafaxine, increased the norepinephrine (NE) concentration in the prefrontal cortex.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Vagus+nerve+stimulation+increases+norepinephrine+concentration+and+the+gene+expression+of+BDNF+and+bFGF+in+the+rat+brain&btnG=

The alpha2 receptor couples to the Gi/o protein. It is a presynaptic receptor, causing negative feedback on, for example, norepinephrine (NE). When NE is released into the synapse, it feeds back on the alpha2 receptor, causing less NE release from the presynaptic neuron. This decreases the effect of NE. There are also alpha2 receptors on the nerve terminal membrane of the post-synaptic adrenergic neuron.
Actions of the alpha2 receptor include:
- decreased insulin release from the pancreas
- increased glucagon release from the pancreas
- contraction of sphincters of the GI-tract
- negative feedback in the neuronal synapses - presynaptic inhibition of norepinephrine release in CNS
- increased platelet aggregation
- decreases peripheral vascular resistance
alpha2 agonists (see actions above) can be used to treat:
hypertension – decrease blood pressure-raising actions of the sympathetic nervous system
alpha2 antagonists can be used to treat:
impotence – relax penile smooth muscles and ease blood flow
depression – enhance mood by increasing norepinephrine secretion
https://en.wikipedia.org/wiki/Adrenergic_receptor

Individual actions of the alpha2 receptor include:
- Mediates synaptic transmission in pre- and postsynaptic nerve terminals
- Decrease release of acetylcholine
- Decrease release of norepinephrine
- Inhibit norepinephrine system in brain etc.
Yohimbine is a relatively selective alpha2 blocker that has been investigated as a treatment for erectile dysfunction.
https://en.wikipedia.org/wiki/Alpha-2_adrenergic_receptor

The tetracyclic antidepressants mianserin and mirtazapine are alpha2 blockers. Mechanistically, alpha2 blockers increase adrenergic, dopaminergic and serotonergic neurotransmitters and induce insulin secretion, decreasing blood sugar levels. Withdrawal from alpha2 blockers can be difficult or dangerous as the global downregulation of neurotransmitters may cause symptoms of depression and other neurological problems, and increased blood sugar levels together with decreased insulin sensitivity can cause diabetes. Moreover, reduced microcirculation together with adrenaline supersensitivity in organs such as liver can occur.
https://en.wikipedia.org/wiki/Alpha-2_blocker

Rauwolscine is a central nervous system stimulant, a local anesthetic and a vague aphrodisiac.
Rauwolscine acts predominantly as an alpha2-adrenergic receptor antagonist. It has also been shown to function as a 5-HT1A receptor partial agonist and 5-HT2A and 5-HT2B receptor antagonist.
https://en.wikipedia.org/wiki/Rauwolscine

Secondary amines (nortriptyline and desipramine) enhance inhibition of norepinephrine reuptake and have a more favorable side-effect profile than the tertiary amines, but these can cause irritability and disturbed sleep. Tertiary amines may be beneficial for patients with insomnia and secondary amines for patients with chronic fatigue. Serotonin- and norepinephrine-reuptake inhibitors (venlafaxin, milnacipran and duloxetine) exert balanced inhibition of reuptake of serotonin and norepinephrine that can be dose-dependent.
https://sci-hub.st/https://www.tandfonline.com/doi/abs/10.2217/pmt.13.50

Duloxetine and milnacipran, dual serotonin transporter (SET) and Norepinephrine Transporter (NET) inhibitors approved to treat major depressive disorder, were effective in relieving chronic pain conditions such as fibromyalgia, osteoarthritis, and diabetic neuropathy. Venlafaxine, also approved for the management of major depressive disorder, anxiety disorder, and panic anxiety, is used off label for the management of neuropathic pain.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Novel+approaches%2C+drug+candidates%2C+and+targets+in+pain+drug+discovery&btnG=

Activation of alpha-2 receptors by agonists such as brimonidine have more recently been shown to enhance survival of retinal neurons after many types of injuries and insults. There are many pathways activated by alpha-2 receptors that might be involved in raising a neuron’s resistance to stress/injury. These include the activation of intracellular kinases that enhance cell survival and the inhibition of glutamate release and calcium influx into cells.
https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0039625701002065

Stimulation of the alpha-2 adrenergic autoreceptor by norepinephrine in the synaptic cleft, or by an alpha 2 adrenergic receptor agonist such as clonidine, decreases NE impulse flow and turnover and induces behavioral sedation. Conversely, the alpha-2 adrenergic antagonists, yohimbine and piperoxane, increase NE impulse flow and turnover and cause behavioral activation.
There is evidence that the sensitivity of postsynaptic alpha-2 adrenergic receptors is decreased in depressed patients.
REM sleep deprivation reduce alpha-2 adrenergic autoreceptor sensitivity.
https://sci-hub.st/https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/abs/alpha2-adrenergic-receptor-sensitivity-and-the-mechanism-of-action-of-antidepressant-therapy/79D17DED58362466CF79267B2E0EE646

Because this agent increases forearm blood flow, yohimbine might be useful in treating the orthostatic hypotension and ischemic vascular disease that results from the autonomic insufficiency common in patients with diabetes mellitus.
The a1-adrenergic receptors are found mainly on blood vessels, and when stimulated by endogenous ligands such as norepinephrine, cause vascular smooth muscle to contract and vascular resistance and blood pressure to increase. The a2-adrenergic receptors are found on platelets, in the vasculature, and on presynaptic neurons. Activation of presynaptic a2-adrenergic receptors results in a decrease in catecholamine release from nerve terminals and the adrenal medulla and a decrease in blood pressure. Alternatively, antagonism of presynaptic a2-adrenergic receptors results in an increase in catecholamine release. It has been demonstrated that endurance training increases the number of a2-adrenergic receptors.
https://www.ahajournals.org/doi/pdf/10.1161/01.hyp.15.6.877

Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment.
Detumescence of the erect penis is initiated by adrenergic agonist stimulation. Adrenergic stimulation results in contraction of the cavernosal arteries with reduced cavernosal arterial inflow as well as contraction of the trabecular smooth muscle leading to collapse of the lacunar spaces. The resultant loss of corporal veno-occlusive function leads to detumescence. The role of the adrenergic neuroeffector system as a mediator of detumescence is noncontroversial. Intracavernosal administration of adrenergic agonists initiate detumescence and have become a routine treatment for prolonged erection.
Physiologic and/or psychologic-mediated catecholamine release may occur secondary to pain associated with Peyronie's disease, prostatitis, epididymitis, or non-genital pain such as headache.
Adrenergic blockade might prolong the duration of the erection initiated by sexual stimulation. Catecholamine release during sexual activity may explain early loss of erection in some men.
One pathway was by direct antagonism of alpha-1 and -2 receptors agonists, at the receptor level, resulting in reduced intracellular calcium release and inhibition of contractility. The other mechanism was probably by an indirect, functional antagonism, in which phentolamine enhanced nitric oxide efficiency in relaxing trabecular smooth muscle.
https://sci-hub.st/https://www.nature.com/articles/3900502

Plasmalogens-deficient mice (GNPAT knockout) showed reduced release of norepinephrine upon high-intensity stimulation in the hippocampal and cortical regions. Plasmalogens deficiency in these animals further manifested as multiple neurobehavioral deficits, such as increased stereotypy, impaired social interaction, and abnormal marble burying.
https://www.sciencedirect.com/science/article/pii/S0361923023001272

Ruscus aculeatus (Butcher's Broom) as a Potential Treatment for Orthostatic Hypotension
Ruscus aculeatus is an alpha-adrenergic agonist that causes venous constriction by directly activating postjunctional a1- and a2-receptors, in turn stimulating the release of noradrenaline.
https://www.liebertpub.com/doi/abs/10.1089/acm.2000.6.539

Progecitor, you agreed to curtail your massively lengthy posts.

Your post quoted above (reduced to 1/3 of our normal text size) shows you have **not** cut back the length of your posting - - as you agreed.

It’s not fair to the other 1,500 forum members who deserve a “voice” and can easily be intimidated by someone posting excessively lengthy “tutorials”, for lack of a better description.

It is not good forum etiquette.

Why Lengthy Posts Are Discouraged
   1.   Attention Span: Most users have limited time and attention. Long posts can be overwhelming and may deter readers from engaging with your content.
   2.   Clarity: Concise messages are often clearer. Lengthy posts can dilute your main points, making it harder for readers to grasp your arguments or questions.
   3.   Engagement: Shorter posts tend to invite more responses. Users are more likely to reply to a post that is easy to read and understand.
   4.   Scrolling Fatigue: In forums, excessive scrolling can lead to fatigue. Users may skip over long posts altogether, missing valuable insights.

Progecitor, by keeping your posts concise and engaging, you contribute positively to the forum environment, making it enjoyable for everyone involved.

Remember, POISCenter.com’s goal is effective communication that fosters discussion and community!

[demografx]

…add a word document as an attachment…

Thanks for the suggestion! I did so!

Research quotes to show how…may affect POIS:
See in the attached document!
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Above color emphases are mine - Demo

Thank you, Progecitor & Aladin.