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List of Biochemical Causes for Irritability

Hip

Senior Member
Messages
17,824
Irritability (a low threshold for annoyance) is a medical symptom that some ME/CFS patients experience, and is even listed in the CDC Holmes criteria definition of CFS, as a possible accompanying symptom of CFS.

Irritability might involve grumpiness, crankiness, petulance, short-temperedness, anger, annoyance, etc.

In my case, at one stage my irritability was so severe that when someone in my house would say "hello, good morning" to me, I would become incredibly irritated at them — almost fuming — for no reason whatsoever. They were being perfectly pleasant, but I would feel a wave of intense irritability in response to any friendly and normal gestures or comments people made.

If someone made a cup of tea, it would really irritate me! If someone turned on the televsion, it would irritate me! If someone breathed in, it would irritate me!

I had to constantly bite my lip, because I was so irritable at everything, for absolutely no good reason, that I wanted to scream at people, or direct very cutting and acerbic comments to them. Obviously there was a major problem in my brain causing this irritability symptom, because I am normally a tolerant and laid back individual.

Unless you have experienced irritability like that, you have not idea how severe it can become. Irritability can be a significant medical symptom.


In order to try to reduce my irritability levels, I have been collecting information on possible biochemical causes of irritability, and possible treatments for irritability. One of the best treatments by far that I found to treat my irritability is very low dose amisulpride (12.5 mg daily), a drug which is further detailed below.

Here is my list of biochemical causes for irritability:

Acidosis.
Systemic acidosis is when the body is too acidic.
Possible treatment: an alkalizing diet; a quarter teaspoon of sodium bicarbonate daily, taken away from meals.

Lactate build-up in muscles.
Possible treatment: as above: an alkalizing diet; a quarter teaspoon of sodium bicarbonate daily, taken away from meals.

High ammonia. Ref: 1
Possible treatment: L-ornithine helps detoxify ammonia, as does L-arginine and L-citrulline.

High TNF-alpha. Ref: 1
Possible treatment: supplements that lower TNF-alpha include: cat's claw (potent), vinpocetine (potent), taurine (potent), evening primrose oil, ginger, chondroitin sulfate, magnesium, fish oil, and many others.

High IL-10. Ref: 1
Possible treatment: One drug which reduces IL-10 is tenofovir, which is also often beneficial for ME/CFS.

Low serotonin due to the Interferon-induced breakdown of tryptophan.
Low serotonin can cause depression or irritability. Tryptophan is needed to make serotonin. Tryptophan is broken down by the enzyme IDO (indoleamine-2-3-dioxygenase). Interferon stimulates the activity of the IDO enzyme, causing increased tryptophan breakdown. Hence interferon can cause depression or irritability. Since interferon gamma is generated when the immune system is in Th1 mode, the use of Th1 boosting supplements may also cause increased tryptophan breakdown, leading to depression or irritability.
Possible treatment: Stop taking supplements that boost the Th1 mode, such as Astragalus, inosine, beta sitosterol, and transfer factor. Aspirin, propolis, resveratrol and lemon balm reduce tryptophan breakdown, so may increase serotonin and thus reduce irritability. Serotonin boosters like high dose inositol (15 grams daily) or saffron may help.

Hyperthyroidism (overactive thyroid).
Possible treatment: antithyroid medicines are used for mild hyperthyroidism.

Low iodine.
Iodine deficiency can cause irritability symptoms. Ref: 1
Possible treatment: kelp or some other iodine-containing supplement.

High prolactin.
Possible treatment: pantethine can reduce prolactin, as can chasteberry (agnus castus) herb, and zinc with vitamin B6.

Low testosterone.
In men, low testosterone may cause irritability. Ref: 1
Possible treatment: tribulus terrestris herb will boost testosterone production; nettle leaf herb will increase the amount of free testosterone (the active form of testosterone).

High DHT (dihydrotestosterone).
High DHT can also cause a loss of hair.
Possible treatment: astaxanthin, saw palmetto extract or beta sitosterol will lower DHT.

High cortisol, or low cortisol.
I read that both high or low cortisol can cause irritability, although not from any reliable sources.
Possible treatment for high cortisol: phosphatidylserine works well to reduce cortisol levels. Holy basil herb (Ocimum tenuiflorum) also lowers cortisol. The anti-fungal ketoconazole is a potent reducer of cortisol, but doctors are prescribing this less now, due to liver damage side effects in rare cases.
Possible treatment for low cortisol: perhaps low-dose hydrocortisone 5 to 20 mg daily.

Low blood sugar.
This typically occurs first thing in the morning
Possible treatment: presumably a snack of slow burning carbs.

High histamine
High histamine levels can cause irritability.
Possible treatment: antihistamine tablets.

High follicle stimulating hormone (FSH) and high luteinizing hormone (LH) levels can cause irritability.
Possible treatment: progesterone cream can lower the amount of FSH and LH hormones released.

High sodium levels can cause irritability. High sodium may come from high levels of salt (sodium chloride) in the diet; or perhaps from high amounts of supplements like sodium ascorbate or sodium bicarbonate.
Treatment: reduce sodium intake.

Vitamin B2 (riboflavin) deficiency can cause irritability.
Treatment: supplement with vitamin B2.

Vitamin B6 deficiency can cause irritability.
Treatment: supplement with vitamin B6.

Vitamin B12 deficiency can cause irritability.
Treatment: supplement with vitamin B12.

Magnesium deficiency can cause irritability.
Treatment: supplement with magnesium.



One of the best treatments by far I have found for irritability is very low dose amisulpride (12.5 mg to 25 mg daily). Amisulpride in very low doses is used as an antidepressant.

More info about amisulpride here: Amisulpride — A Multipurpose Drug for ME/CFS

Severe irritability is a common symptom in autism, and the main treatment for this is atypical anti-psychotic drugs such as amisulpride, risperidone (Risperdal) or aripiprazole (Abilify).


Some research has shown that N-acetyl-cysteine can help the irritability in autism, but the research showed this is not quite as effective as atypical anti-psychotics.

Other anti-irritability supplements I found were: vinpocetine 20 mg (must be taken with food), royal jelly 3000 mg, vitamin B2 100 mg, estriol 0.2 mg (estriol comes as a cream you can put on the skin).

I also found that high salt (sodium) intake caused irritability in me. I was taking several grams of salt as a POTS treatment, but had to stop because of the increased irritability it caused.


Irritability has been linked to the dopamine D5 receptor.
 
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sensing progress

Senior Member
Messages
296
Location
Tucson, AZ
I often get irritable after eating anything with sugar in it, however I'm fairly certain its not from hypoglycemia. Any idea what other mechanism it could be? I believe I also have Leaky Gut Syndrome and that it may be related to this.
 

Hip

Senior Member
Messages
17,824
I often get irritable after eating anything with sugar in it, however I'm fairly certain its not from hypoglycemia. Any idea what other mechanism it could be? I believe I also have Leaky Gut Syndrome and that it may be related to this.


Not sure. I'll have to think about it. Are you positive it is not some rebound hypoglycemia? You could test this easily by buying a low cost digital blood sugar level meter (you can get these amazingly cheaply), and testing your blood sugar say every 15 minutes after eating sugar, to see if there is some elevation and then rebound reduction in blood sugar level.

The other thing I can think of is that the sugar is feeding some bad gut bacteria you may have, and causing an adverse reaction?
 

sensing progress

Senior Member
Messages
296
Location
Tucson, AZ
Not sure. I'll have to think about it. Are you positive it is not some rebound hypoglycemia? You could test this easily by buying a low cost digital blood sugar level meter (you can get these amazingly cheaply), and testing your blood sugar say every 15 minutes after eating sugar, to see if there is some elevation and then rebound reduction in blood sugar level.

Fairly sure. The reason I say that is I have a lot of experience with hypoglycemia and that irritability is like a crankiness but it can be controlled if I try hard. This other irritability I sometimes (but not nearly always) get when I eat certain sweet treats is a more profound irritability that feels different and more intense (hard to explain).

The other thing I can think of is that the sugar is feeding some bad gut bacteria you may have, and causing an adverse reaction?

That is a good idea and I think a distinct possibility. Any others have experience with this?
 
Messages
2,565
Location
US
I get irritable from hormonal stuff like birth control pills.

I get irritable from benzos including benadryl which is similar to a benzo. And other CNS depressants.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
I often get irritable after eating anything with sugar in it, however I'm fairly certain its not from hypoglycemia. Any idea what other mechanism it could be? I believe I also have Leaky Gut Syndrome and that it may be related to this.

You could have hyperinsulinemia (abnormally high insulin spikes/level). That can cause some to get very irritable (it can affect my moods if I eat carbs so badly that Ive actually smashed car windows.. I think Im extra sensitive to my own abnormally high insulin levels due to also having MCS?, so the combination of these two together appears to be quite bad for me).

It is possible to have hyperinsulinemia without also having hypoglycemia and it would explain getting irritable after sugar (and possibly other forms of carbs too).

Hyperinsulinemia is tested by 2 hr Glucose tolerance testing but with the insulin levels included. If you do have high insulin... it can also make other symptoms worst too eg I get less sore throats etc now that my doctors have got me on extremely low carb diet. Things like GERD, bloating if you have those, can also be caused solely by this issue.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
PMS tends to be worst in ME/CFS people. That of cause can cause a lot of irritability. (I think we are far more sensitive to all our homones).
.....

Food intollerence reactions can also cause irritability. (one sees that a lot in kids and I guess it probably causes some of us issues too).
 

alice111

Senior Member
Messages
397
Location
Canada
@Hip the first thing you mention is acidosis,how can you tell if this is the problem? also, does potassium bicarb work the same as sodium bicarb? thanks!
 

Gingergrrl

Senior Member
Messages
16,171
Not sure if this has already been said (and I haven't read the entire thread yet) but I had irritability and agitation as part of an over-methylation reaction, dehydration/electrolyte imbalance, hypoglycemia, and as part of the delayed reaction to a horrible reaction to IV saline.
 

Hip

Senior Member
Messages
17,824
@Hip the first thing you mention is acidosis,how can you tell if this is the problem? also, does potassium bicarb work the same as sodium bicarb? thanks!

Not sure how acidosis is measured. You might consider trying a ¼ teaspoon of sodium or potassium bicarbonate each day (either is fine), and seeing if that improves you irritability symptoms. (Bicarbonate by the way seems to dramatically reduce post-exertional malaise: see this thread).

I went through all these potential causes of irritability by trial and error, taking each of the treatments in turn to see if they would improve my irritability symptoms. The only treatments in my above list of that I found reduced irritability a bit was taking DHT inhibitors, and TNF-alpha inhibitors.

DHT can cause male pattern baldness hair loss (androgenic alopecia), incidentally, so inhibiting DHT (and/or inhibiting the enzyme 5-alpha-reductase that makes DHT) can also help reduce this type of hair loss.

My protocols were:

Anti DHT & 5AR protocol:
Astaxanthin 8 mg
Saw palmetto 320 mg
Biotin 2 mg
Zinc 22 mg

Anti TNF-alpha protocol:
Cat's claw (15:1 extract) 200 mg
Chondroitin sulfate 500 mg
Vinpocetine 20 mg
Ginger 1200 mg


However, by far the best treatment for irritability I found was very low dose amisulpride (just 12.5 mg daily, which is very economical). I have taken this daily for several years now, and I still swear by it. It has other benefits too, like reducing sound sensitivity. If I stop taking it, within two days my grumpy irritability returns.
 
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alice111

Senior Member
Messages
397
Location
Canada
@Hip Thank you so much!
How did you know that your DHT was high?

Also, if possible could you explain how amisulpride works? I checked on wiki.. It's a little too much for my foggy brain.. Is it like an antidepressant? Or a benzo?
 

Hip

Senior Member
Messages
17,824
@Hip Thank you so much!
How did you know that your DHT was high?

Also, if possible could you explain how amisulpride works? I checked on wiki.. It's a little too much for my foggy brain.. Is it like an antidepressant? Or a benzo?

I didn't know, and still don't know, if my DHT is high, but I found that DHT lowering medications improved my irritability symptoms a bit. I did not do any testing, I just tried out all the above anti-irritability treatments to see which helped and which didn't.

Amisulpride at very low doses acts as an antidepressant. At normal doses it acts as an anti-psychotic. The reason it acts differently at different dose levels is a little complex to explain, but basically at very low doses amisulpride activates the dopamine D2 and D3 receptors in the brain (via an autoreceptor mechanism), but at normal doses it does the opposite and blocks the dopamine D2 and D3 receptors.

There may be some risks linked to amisulpride (see the thread), but these I hope will be minimized due to the very low doses used.
 

Gondwanaland

Senior Member
Messages
5,092
You might consider trying a ¼ teaspoon of sodium or potassium bicarbonate each day (either is fine)
I had extreme low blood pressure from as little as 30mg potassium bicarbonate. @Sidereal reported the same reaction. OTOH I don't get this reaction from sodium bicarb.
 

Hip

Senior Member
Messages
17,824
@alice111
I cannot see any direct measure of DHT (dihydrotestosterone) in that report, but 5AR (5-α-reductase) is measured, and 5AR is the enzyme that converts testosterone into DHT, so 5AR levels might possibly give some indication of DHT levels, but I don't know for sure.
 

alice111

Senior Member
Messages
397
Location
Canada
@Hip I am wondering if you wouldnt mind taking a look at my latest hormone tests?
I don't really know what to make of it, and it seems like you are really knowledgeable on pathways and enzymes etc
it would seem to me that something is messed up, and i have an overactivity or underactivity of some enzymes... although i cant make head or tails. what is particularly strange is that I am supplementing with progesterone but it seems to all be converting down the wrong path!
here is where I posted my test results : http://forums.phoenixrising.me/inde...-help-me-interpret-results.35784/#post-566050
ps totally understand if you dont have the time to look, and no worries , just thought id throw it out there!
thanks so much for all your help with everything you have replied so far :)