Erectile dysfunction Part 1: the solution for your neurotransmitters

It’s predicted that by 2025 300 million men will have erectile dysfunction, yet it’s shown that less than 30% are willing to admit to it.

I’m sure you would agree that it’s because this is a very embarrassing thing to experience and deal with. It’s so to say one of the most embarrassing things. Lucky for me, When I went through ED related issues myself, my wife never made me feel bad and was very understanding and supportive. But none the less, it’s still embarrassing for us and something that definitely needs dealing with.

For men, sexual performance carries an identity and a sense of self-esteem in his society.

If you can’t get it up, you feel like you lose a large chunk of your confidence and manliness. ED can also lead to a reduction in libido and increase anxiety and depression, which, in a feedforward loop, makes the ED worse. In many cases, the wife/partner might even start to think the man is cheating on her, because of his avoidance and lack of performance.

In daily life, it is very easy for men to admit to having a sore throat or hemorrhoids. However, admitting to having erectile dysfunction is contrary to the male ego and especially so if the dysfunction occurs early in life.

It’s not so rare

ED has been thought to be an “old man’s disease”, but new stats are showing that one in four men under that age of 40 complain about ED (R).

It’s even been thought that the prevalence of ED can be as high as 50% in the non-healthy population. ED is one of the first symptoms someone gets when they progress with cardiovascular disease.

The first line of treatment for ED is the blue pill…viagra (sildenafil). Or other nitric oxide boosting drugs such as tadalafil and vardenafil.

Conventional treatments are not very effective

These drugs are generally well-tolerated, but about 5-40% do get symptoms such as headache, facial or chest flushing, dyspepsia, and sinusitis, which are just the most commonly reported adverse side effects.

Topical administration of nitroglycerin has demonstrated only moderate and inconsistent efficacy in improving erectile function, and also has been observed to cause headaches. Similarly, oral L‐arginine supplements in men with ED have yielded inconclusive results and may only be effective in men with reduced exogenous NO production.

In fact, data indicate that 50–80% of men discontinue the use of medical interventions (oral medications, ICIs or VEDs) for erectile dysfunction within 1 year, due to side effects and a desire for a permanent solution (R).

In this article, I want to explain how things work, what can be causing or contributing to ED, and what to do about it. And the goal is to go back to a state when no meds or supplements are needed and you’re just your high libido, naturally capable, competent self.

This article is the first part of a 5 piece series. All parts include:

• Part 1: Erectile dysfunction and your neurotransmitters
• Part 2: Erectile dysfunction and your hormones (such as testosterone, DHT, cortisol, etc.)
• Part 3: Erectile dysfunction and organic issues, such as diabetes, neurological disorders, cardiovascular disease, etc.
• Part 4: Best supplements for erectile dysfunction
• Part 5: Erectile dysfunction and masturbation

How do things work

In the flaccid state (non-erect), the smooth muscle of the penis is contracted. Thus, no extra blood can flow in and promote an erection. So one can see it as a “flexed” state. When it becomes too flexed, as when it shrivels up and back, usually due to stress and low blood sugar, it’s in a very contracted state.

We’ll get into what promotes this contraction in just a bit. Unable to relax is the first “error” in ED.

In order to relax, calcium ions in the cells (which induce contraction), has to be pumped out. Nitric oxide is a main relaxor, but an erection can also be obtained via nitric oxide independent pathways as well.

The result of the ensuing signaling pathways is increased cyclic GMP (cGMP) concentrations, decreased intracellular Ca²⁺ levels and smooth muscle cell relaxation. As the smooth muscle relaxes, blood is able to fill the lacunar spaces in the corpora cavernosa, leading to compression of the subtunical venules, thereby blocking the venous outflow (veno-occlusion). The process is reversed when cGMP is hydrolysed by phosphodiesterase type 5 (PDE5). Erectile dysfunction can occur when any of these processes are interrupted.

So the first step is to get the smooth muscle to relax, the second is to get blood into the penis and the third is to pinch the outflow vein closed so that the blood remains in the penis. Kinda like blood flow restriction training. And yes, you do get a band you can put around the base to prevent blood from flowing out, but that leads to coldness, numbness, loss of color, possible gangrene, etc.

And lastly, sexual activity triggers the bulbocavernosus reflex, causing the ischiocavernous muscles to forcefully compress the base of the perfused corpora cavernosa, resulting in further, or full, rigidity.

As you can see in the pic above, noradrenaline and endothelins promote calcium entry into the cell, which promotes contraction (R). The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin. Aspirin, even in doses of 81mg daily, can have potent anti-platelet effects and can lower endothelin and promote vascular relaxation in the penis.

Noradrenaline also creates ROCK, of which testosterone is an antagonist, which also promotes contraction to maintain the flaccid state.

In the pic above, acetylcholine and non-adrenergic non-cholinergic nerves promote the release of nitric oxide (NO) and inhibit calcium entry, and this promotes relaxation.

Erection upon touch or stimulation is under the control of the peripheral nerves and the lower parts of the spinal cord, and the psychogenic erection is achieved by visual or mental stimuli (fantasies, etc), and uses the limbic system of the brain.

So both the reflex erection and/or psychogenic erection can be involved in ED.

Let’s get into what controls the erection.

What controls the erection

Many things have an influence on erection and I’m going to start with neurotransmitters in this article.

So hang in tight, it’s going to be a fun read.

Central nervous system controls erections

The central nervous system (CNS) consists of two branches, the sympathetic and the parasympathetic.

The sympathetic is what keeps you awake and full of energy, whereas the parasympathetic calms you down and promotes relaxation and sleep.

We want these two to be in balance. Too much sympathetic and we’re an anxious wreck, bouncing off the walls, constantly stressed and sweaty.

Too much parasympathetic and we have no energy, no libido and no drive in life.

The penis is controlled by nerves and loss of neural function can lead to loss of erectile function. Complete numbness, which is a horror story.

Catecholamines such as noradrenaline and adrenaline act as both hormones and neurotransmitters, so that’s why I’m including it together with the other neurotransmitters.

A. Sympathetic nervous system inhibits erections

The sympathetic nervous system promotes the secretion of noradrenaline and adrenaline which inhibit erectile function (R). It promotes contraction of the smooth muscle and vasoconstriction.

Noradrenaline and adrenaline bind to the adrenergic receptors, of which there are 5, namely α1-, α2-, β1-, β2- and β3-adrenergic receptors.

α1 activation induces vasoconstriction and antagonizing it promotes relaxation and erection. Antagonism of α1‐adrenoceptors is a frequent cause of priapism (prolonged erections). Phentolamine is an α1-adrenergic receptor inhibitor that helps to prevent vasoconstriction to maintain an erection.

α2 activation lowers noradrenaline levels, but it is also anti-erection. Inhibiting it, with yohimbine (R) for example, promotes penile smooth muscle relaxation and promotes blood flow. This can increase the ease with which you can be an erection, but will not facilitate one by itself.

Symptoms of too much noradrenaline include:

• short flaccid hang
• finding it hard to get him up
• struggling to keep him up
• great morning wood but great sexual anxiety
• likely excellent response to phosphodiesterase type 5 inhibitors or other NO precursors (R)

Copper is a cofactor necessary for the conversion of dopamine to noradrenaline. Too much copper and you can end up with an excess of noradrenaline. This is why zinc can help so much with sexual anxiety and erection because it lowers copper and noradrenaline. 

Stress is one of the biggest contributors to elevated noradrenaline, so be sure to manage your stress to lower excess noradrenaline.

• How to manage your stress and cortisol
• How to interpret your cortisol blood tests accurately

A short story about myself. At the beginning of my marriage, I used to have occasional trouble getting him up and maintaining an erection. This made me very mad of course, which in turn just further made things worse. During that period I was under a lot of stress, in a caloric deficit and was doing intermittent fasting. These things stimulate the adrenals to release noradrenaline, adrenaline, and cortisol, all of which promote ED.

B. Parasympathetic nervous system promotes erections

The parasympathetic nervous system is the opposite of the sympathetic nervous system. Acetylcholine is the main parasympathetic neurotransmitter.

Acetylcholine produces concentration-dependent relaxation of erectile tissues that has been precontracted with norepinephrine. Acetylcholine counteracts the effect of noradrenaline and may also suppress the release of norepinephrine (R).

Getting enough choline and vitamin B1 in through the diet can help the body produce enough acetylcholine for proper erections. 

You know that feeling where you’re just so tired (but can still get a good erection) and just want to lay in bed hoping your significant other will do all the work?…that’s most likely excess parasympathetic activation, elevated GABA and/or low pregnenolone-S and DHEA-S (more of that in part 2).

Glutamate is pro-erection but can be dangerous

Glutamate is an excitatory neurotransmitter that promotes wakefulness, focus, learning, libido and also erection.

Too much glutamate and one can start to suffer from anxiety, racing thoughts, pain hypersensitivity, and neurological pain because glutamate is a neurotoxin in high amounts.

Glutamate can bind to a host of receptors, but it promotes erections through the acting on the AMPA and NMDA receptors (R). Activation of the NMDA receptor stimulates the same oxytocinergic pathways as dopamine and both these receptors increase NO levels. Which in turn promotes relaxation of the smooth muscles and stimulates erection.

Ketamine, which antagonizes the NMDA receptor, can cause the infamous droopy dick.

Substance P, co-released with glutamate, also acts as a neurotransmitter and is a potent vasodilatory and erectogenic agent (R). However, it promotes inflammation, reduces pain tolerance and promotes male aggression.

Together, excess glutamate and substance P can cause neurological damage and close to 100% of people with neuropathy experience ED.

So glutamate is needed, but an excess is bad. You can lower excess glutamate by increasing energy production (low ATP leads to elevated glutamate), using taurine, glycine, magnesium, theanine, valerian, etc.

Things that lower noradrenaline and glutamate can also promote relaxation and reduce sexual anxiety, which as a result will improve erectile function. But lowering them too much might take your libido away, so it’s good to keep a balance.

Serotonin is disastrous for erections

Oh, the beloved serotonin.

It won’t be so beloved once you’ve seen the facts.

Serotonin, in excess, is known to inhibit libido and erections. Up to 80% of people, in young patients in particular, on SSRI drugs report sexual dysfunction as one of the most relevant side effects (R, R). That is exactly why up to 90% of people discontinue SSRI therapy. They just can’t handle the feeling of no desire, poor erections and blunted or absent orgasm. Awful I tell you…but don’t take my word for it, listen to the guys who’ve used SSRI drugs before.

Serotonin can inhibit erections by:

• inhibiting nitric oxide synthesis (R)
• lowering dopamine release
• increasing prolactin
• increasing renin (which promotes vasoconstriction and inflammation)
• stimulating the adrenal axis (CRH, ACTH and cortisol) through activation of the 5-HT2A receptor (R, R).

Various serotonin antagonists, such as mianserin, ketanserin and trazodone, which inhibit the 5-HT2A and 5-HT2C receptors improve erections and prevent premature ejaculation (R, R)

Additionally, mianserin is an α2-adrenergic receptor antagonist and trazodone is an α1-adrenergic receptor antagonist, which helps with erections (R, R, R)

The serotonin receptor 5-HT3 also appears to reduce erectile function and blocking it improves it (R). Ondansetron, a 5-HT3 antagonist, used to treat nausea, is able to promote erection by aiding in pinching the outflow vein closed, which promotes blood pooling in the penis (R).

Ginger, which is a natural 5-HT3 antagonist can also aid in erections, but promoting blood flow and blocking 5-HT3.

Lastly, the serotonin receptor 5-HT4 might also be anti-erection, and blocking it can have pro-erection effects (R). Lysine is a natural amino acid with potent 5-HT4 antagonistic properties and could aid in erections.

It appears that the negative effects of excess serotonin induced by SSRIs are long-lasting as only 5.8% of patients experienced complete recovery within 6 months, whereas 81.4% showed no improvement at all by the end of that period (R).

Opioids inhibit erection

Natural opioids found in the body include endorphins, enkephalins, and dynorphin.

Other opioids include drugs, but can also be found in food. The three most potent natural opioids are found in poppy seeds, wheat and milk. Other foods that can also have a pro-opioid effect are oats, spinach and cocoa powder, but it’s much weaker than the opioids found in wheat and milk.

Opioids significantly mess with boner capacity (R). 

Coffee contains natural anti-opioid compounds (which is not the caffeine) as well as phosphodiesterase-5 inhibitory properties, so coffee can have pro-erection effects.

Histamine can help with erection

Histamine is another excitatory neurotransmitter and can promote vasodilation and smooth muscle relaxation in the penis independent of nitric oxide (R). The effect is mostly due to the H2 activation and H1 receptors antagonism (R). H2 antagonists such as cimetidine are known to cause impotence in men.

Injecting histamine can promote full erections in some people and partials in most (R). Too much copper in the body can contribute to low histamine, so lowering copper in the body with zinc, vitamin C and molybdenum can lower copper and increase histamine. Niacin and niacinamide can also help increase histamine by inhibiting its breakdown through methylation.

Kutaja bark extract (Holarrhena antidysenterica), an H3 antagonist, is also able to increase histamine and dopamine and might be effective for promoting erection.

GABA could prevent proper erections

GABA has inhibitory effects on erection, so any pro-GABA supplements or drugs might be best left for after action-time.

Pregnenolone-sulfate and DHEA-sulfate are potent GABA antagonists and as a result, can reduce excess fatigue and can thus have pro-erectile effects.

The fastest way to get pregnenolone-S and DHEA-S up is to supplement 100mg pregnenolone with 25mg DHEA for 30 days.

Melanocortins & Agouti-related peptides (AgRP) involvement in erections

You might never have heard of there neurotransmitters, but they do play a role. 

Melanocortin receptors are stimulated by the melanocyte-stimulating hormone (MSH) which increases the metabolism, sex drive, erections, lowers appetite and promotes skin tanning.

AgRP is the opposite and stimulates appetite and suppresses the metabolism and erections. AgRP levels increase when ghrelin, the hunger hormone, increases. Many growth hormone drugs/peptides act as ghrelin receptor agonists and might increase AgRP which contributes to ED. However, the increase in IGF-1 due to these peptides might offset the side-effects. For example, hexarelin has pro-erection properties (R).

MSH is fully active when you’re eating a good diet to support the metabolism, are sleeping well, getting lots of sunlight, not being stressed, etc.

Bremelanotide, a synthetic analog of α-MSH, is currently under development for the treatment of sexual dysfunction. Other analogs include Melanotan and Melanotan II.

AgRP becomes elevated when you’re fasting, had a bad night’s sleep, are overtraining, eating too little, stressing, etc.

Dopamine is pro-libido and erection

Dopamine, together with histamine, promotes drive in life, motivation, desire, energy, exploration, etc. It makes us feel euphoric and it improves erectile function.

Dopamine is a major modulator of sexual function and is the primary prolactin antagonist. Prolactin lowers testosterone levels, inhibits DHT formation and reduces libido and erections. Prolactin, similar to serotonin, is also able to modulate dopaminergic function in specific brain regions and inhibit dopamine control in the hypothalamus (R). More on prolactin in part 2. 

Dopamine is thought to regulate erection by acting on oxytocin containing neurons in the paraventricular nucleus of the hypothalamus, where prolactin has an inhibitory effect (R).

Dopamine can even induce an erection in the presence of a NOS inhibitor (R).

This just shows how important dopamine is for erections and sexual function.

Dopamine agonist treatment in Parkinson’s disease is frequently accompanied by the clinical observation of hypersexuality (R).

Some of the safer dopaminergic drugs that can have the best effect on erections include lisuride, metergoline, amantadine and selegiline (R, R).

Of the natural herbs, Catuaba bark extract might be a great option, as it not only increases dopamine but also promotes erection quality and enhances libido. Check out BrainX, which contains a great blend of ingredients that can enhance libido and erection.

For a complete guide on increasing dopamine, check out my article on that:

> How to increase dopamine

Mental disorders

ED is very prevalent in men with mental disorders, such as depression and anxiety. Rates of depression in men with erectile dysfunction are reported to be as high as 56%, if not higher.

Anxiety might be even worse as the mind has a direct effect on erection. The more anxious someone is, the less likely they’re going to get a full or lasting erection.

This anxiety increases a man’s focus on the firmness of his erection, leading to self-consciousness and cognitive distractions that interfere with arousal and contribute to poor performance. And this bad experience just contributes to further anxiety, depression and low self-confidence.

Your neurotransmitters directly influence your mindset and mood. Excess glutamate and sympathetic nervous system activation contribute to anxiety.

Excess cortisol release, low DHEA-S, low testosterone and dopamine and high serotonin and prolactin can contribute to depression and impotence. More on hormones in part 2 of this series.

So focusing on optimizing the right neurotransmitters can do wonders for your mood and erections.