Irritability (a low threshold for annoyance) is a medical symptom that some ME/CFS patients experience, and is even listed in the CDC case 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: Tenofovir potently reduces IL-10. 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. Other effective 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). 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. I also found that high salt intake caused irritability. 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.