Serotonin promotes stress. Simple as that.
Stress is the evil knievel when it comes to health issues. But the worse of all is that we induce it willingly with a drug.
Serotonin is a stress hormone. It goes up during stress. And it’s not good in any way. Let’s say you get hurt or are scared, then serotonin might temporarily blunt your feelings but is there to make you afraid of whatever hurt/scared you. That’s why people get PTSD from chronic stress and elevated serotonin…and in this case, PSSD.
It should actually just be called SSD for serotonin-induced sexual disorder.
PSSD is a syndrome where people get sexual dysfunction after stopping SSRI drugs. However, most people actually get sexual dysfunction while still on the drug. The sexual function just persists after they stopped.
Stress and magnesium
Elevated serotonin increases cortisol, glutamate, nitric oxide, inflammation and noradrenaline in the brain just to name a few.
Magnesium is an intracellular mineral, which shifts to the extracellular space where is plays a protective role in order to diminish the adverse effects of stress. When magnesium is shifted to the extracellular shape, we excrete more magnesium through our urine. If the stress is chronic, as with SSRI use, we can easily induce a magnesium deficiency.
Moreover, stress and hypomagnesemia potentiate each other’s negative effects in a veritable pathogenic vicious circle.
A low magnesium to calcium ratio augments the release of catecholamines in response to stress. Fatty acids, released from adipose tissue, resulting from adrenergic-induced lipolysis, form undissociated magnesium soaps which further exacerbates magnesium depletion.
Magnesium deficiency also favours the release of vasoconstrictive and platelet aggregating factors (derived from fatty acid metabolism and endothelium), increases the thromboxane B2 to prostaglandin I2 (TxB2/PgI2) ratio and enhances intravascular blood coagulation. In short, low magnesium promotes blood clots and vasoconstriction, well in line with high serotonin.
…the concentration of circulating vasoconstrictor hormones, such as angiotensin, serotonin and acetylcholine, are increased when extracellular magnesium is lower than normal.Reference
In other words, low magnesium is synonymous with high serotonin symptoms.
Stress wastes magnesium. Serotonin increases cortisol (5-HT2C activation promotes CRF release, which contributes to stress and neuropathic pain (R)) and noradrenaline, which increases magnesium excretion and the formation of undissociated magnesium soaps.
Low magnesium and stress
In short, here is how the stress cascade works:
A stressor (either physical or psychological) initially activates the hypothalamic-pituitary- adrenal (HPA) axis and the autonomic nervous system. Activating these systems leads to the release of catecholamines from sympathetic nerves and the adrenal medulla, and of corticotropin-releasing factor (CRF) and vasopressin (AVP) from parvocellular neurons. Seconds later, adrenocorticotropic hormone (ACTH) is secreted from the anterior pituitary gland and stimulates release of glucocorticoids from the adrenal cortex.
CRF is a neurotransmitter involved in the coordination of the endocrine, autonomic, behavioral and immune responses to stress, and whose administration elicits stress-like effects (R).
- Leads to enhanced NMDA activation. Glutamate-stimulated CRF release is antagonized by the magnesium. Magnesium also stimulates the Na+/K+ATPase, which decreases CRF-receptor sensitivity (R).
- CRF acted through CRFR1 to sensitize 5-HT2A-mediated signaling and anxiety behaviors thereby linking CRF-mediated stress responses to anxiety and depression (R).
- Results in enhanced ACTH release and modulates adrenocortical sensitivity to this hormone (R). As intracerebroventricular administration of angiotensin II (ATII) increases the secretion of ACTH and AVP (vasopressin) via CRF, it is presumed that magnesium induces a suppression of HPA-axis activity, at least partially, through antagonism of ATII effects.
- Is associated with elevated brain noradrenaline (R) and increased catecholamine release in response to noise stress in rats (R). Also, it has been proven that magnesium exerts a direct suppressive effect on locus coeruleus (the area in the brain that releases noradrenaline) activity and that poor magnesium status increases sensitivity to stress.
- Leads to chronic stress, which causes a reduction in dopaminergic transmissions in the prefrontal cortex (R).
- Reduces 5-HT1A sensitivity. A lot of people with PSSD tend to have reduced 5-HT1A sensitivity and magnesium has been shown to have a direct enhancing effect on 5-HT1A serotonin-receptor transmission (R).
- Low 5-HT1A activation (due to desensitization) causes overactivation of the NMDA receptor (R).
- Results in excess prolactin release during stress. If stress is continuous, prolactin might be chronically elevated (R).
- Might result in reduced oxytocin receptor binding. Magnesium acts as a positive allosteric modulator for oxytocin binding to the receptor, and in this way facilitates the neuropeptide’s action to alleviate stress (R).
- Can result in low BDNF levels. Serotonin can cause brain damage in excess, so restoring BDNF can aid in brain regeneration (R).
- Exacerbates lipid peroxidation, catecholamine auto-oxidation and DNA damage (R).
Magnesium and PSSD
Sexual dysfunction symptoms of PSSD include:
- Erectile dysfunction
- Premature ejaculation (some might have delayed ejaculation)
- Penile numbness
- Low libido
- Watery semen
Other non-sexual side effects include:
- Anxiety and fear (sometimes anhedonia instead)
- ADHD symptoms
- Cold hands and feet
- Trouble sleeping
These symptoms correlate with sympathetic nervous system overactivation, excess stress and elevated serotonin and prolactin.
What does these inversely correlate with? That’s right… Magnesium.
How magnesium helps PSSD:
- Magnesium exhibits simultaneous beta-agonist effects and alpha-adrenergic antagonist (alpha-blockers are commonly used to prevent premature ejaculation (R)) actions (R). This leads to higher libido, better erections and longer endurance. Magnesium deficiency can lead to ED and premature ejaculation (R).
- Overactivation of the sympathetic nervous system (in a low magnesium state) inhibits erections but stimulates ejaculation.
- Thus, in this state, erections will be subpar and you’ll be prone to premature ejaculation.
- It bears repeating – low magnesium is synonymous with overactivation of the sympathetic nervous system.
- Magnesium sensitizes oxytocin receptor binding. Oxytocin increases penile sensitivity and oxytocin receptor antagonists are commonly used for premature ejaculation. But instead of promoting premature ejaculation, oxytocin rather increases penile sensitivity for more pleasurable orgasms.
- Low magnesium can lead to orgasm without much feeling/pleasure – Anorgasmia
- Magnesium might reduce the refractory period and increase semen volume.
- Magnesium sensitizes the 5-HT1A receptor, which can restore sexual function if desensitized by SSRI drugs.
- Better 5-HT1A sensitivity (if it’s the autoreceptor) can help to lower serotonin as serotonin also contributes to the inhibition of erection and/or ejaculation (R).
- Magnesium stimulates the reward system (dopamine center of the brain) and is helpful for treating anhedonia in patients with major depression (R).
- Decreased levels of magnesium give rise to vasoconstriction from increased thromboxane level, increased endothelial intracellular calcium, and decreased nitric oxide. This may lead to poor erections and premature ejaculation (R). Magnesium also prevents hypertension as it’s an angiotensin II receptor antagonist.
- Promotes better sleep.
- “Mg depletion is associated with decreased melatonin and its supplementation alleviates the symptoms (Billyard et al., 2006; Depoortere et al., 1993; Held et al., 2002). In elderly subjects, Mg administration (10 mmol and 20 mmol each for 3 days followed by 30 mmol for 14 days) significantly increased slow wave sleep, renin levels during the total night, and aldosterone levels in the second half of the night, but decreased cortisol levels in the first part of the night.” (R)
Magnesium is absolutely crucial for proper health and is most likely low in people with PSSD due to serotonin’s ability to waste magnesium.
As a side note, magnesium is easily lost in a hypothyroid/excess stress state, so taking a lot isn’t necessarily the answer.
Taking is with thyroid and/or aspirin is the key to retaining magnesium and combating stress.
A simple stack is to take:
- 1-2g magnesium glycinate/taurate
- 1.5g aspirin or 1/3 tsp sodium salicylate
Then you can take this stack x2-3 daily.
You can always make you own magnesium salicylate by mixing 1/2 tsp magnesium carbonate with 1/2 tsp sodium salicylate in 1/2 cup water and then drink a 1/3 of that x3 daily.
If you want to learn more about PSSD, check out my other 2 articles on the subject.
- PSSD: The why and the how to get it fixed
- Drugs, herbs and strategies to resolve SSRI-induced sexual dysfunction
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I have PSSD (Post-SSRI sexual dysfunction). It is rare condition that very few people have even looked into. Hans is aware of the main mechanisms behind it and we were able to brainstorm and find the likely root cause (something I wouldn’t have been able to identify on my own). There is now a path to follow which may very well bring me back to human normality. I’ve already began to experience relief in the past few weeks so things are looking good.
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