Irritability (a low threshold for annoyance) is a symptom some ME/CFS patients experience, and is a listed symptom in the CDC Case Definition of CFS. I have been collecting information on possible biochemical causes of irritability. Here is my list of biochemical causes for irritability as it stands so far: 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 TNF-alpha 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. Possible treatment: none found. 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. Possible treatment: 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. 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 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). 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 this is not quite as effective as atypical anti-psychotics. Irritability has been linked to the dopamine D5 receptor.