I have a new Paradigm to propose for the cause of CFS in some people (it also applies to some other illnesses): Gut dysbiosis with organisms which make histamine in the body is the cause of CFS in some people. This is because organisms in the gut that produce histamine can cause a chronic shortage of SAMe or S-Adenosyl methionine, and low levels of SAMe can cause extreme fatigue. One of my son's experienced extreme fatigue for over a year from this cause. How does this happen? The needs of the body for SAMe can vary through the day, yet the mechanism for changing the amount of SAMe produced by the body takes more than 24 hours to significantly change the amounts of the enzymes that are responsible for recycling homocysteine into SAMe: methionine synthase and methylenetetrahydrofolate reductase (MTHFR). If the level of SAMe rises too high, then methionine synthase and MTHFR are inhibited, and CBS is increased, because SAMe inhibits its own production.1 This is how SAMe is regulated in the body. If a person has histamine producing bacteria in the gut, then the bacteria will produce more histamine during the hours after eating, and less histamine during times of sleep when the protein supplying histadine, the precursor of histamine, is less abundant. Sometimes the person will feel better in the morning before eating, and sometimes not. The unusual fluctuations make it difficult for the body to regulate the histamine levels. As the histamine levels drop during the non-eating part of the day, SAMe level rises since less is being used by the enzyme histamine N-methyltranferase to donate a methyl group to degrade histamine. This triggers the inhibitory effect on the production of methylation cycle enzymes leading to chronically low SAMe during the part of the day when histamine levels are higher. See Low SAMe.jpg So how do we maintain levels of SAMe that are high enough for our highest daily needs without triggering the inhibiting response during the part of the day when we need less? I would suggest that one unacknowledged function of niacin is to be a methyl sponge to keep the levels of SAMe from getting high enough to trigger the inhibition. If free niacin floating in the blood isn't harmful, and I believe that it isn't (There have been cases of liver damage from high doses of time released niacin, but none from regular niacin or niacinamide, unless you believe that elevated liver enzyme are equivalent to liver damage.) in the amounts that are needed for the methyl sponge function (perhaps up to 2.5 grams a day for some people), then I believe that the metabolism of niacin is a sufficiently low priority job for SAMe that it does its other more important jobs first and then if there is excessive SAMe, it is used to rid of extra niacin. So here is another new theory: Niacin functions as a buffer for S-Adenosyl methionine (SAMe) in order to assure adequate levels of SAMe for the highest need of each day, by preventing inhibition of methionine synthase and MTHFR by high levels of SAMe during periods of lowest need of each day. See with Buffer.jpg This niacin buffer will also prevent any “overmethylation” symptoms such as anxiety. My suggested treatment for this problem is as follows: Niacinamide, 1.5 grams before bed with or without food. Methyl folate or folinic acid, 3 mg with breakfast, 3 mg with dinner. Methyl B12, 1000-10000 mcg sublingual 3 times a day. Edit 11/12/2013 - Methionine 1-2 grams a day for the first 3 days then gradually less to 500mg. Added 11/14/2013 - Zinc (picolinate is good, or whatever type works for you) 30-50 mg more than you already take unless you feel that you are already taking enough. This is especially important if you have ever had problems with leaky gut. Added 11/13/2013 - P5P (activated B6) 25-100 mg a day. At the beginning of supplementation a surge of energy may occur for a couple of days followed by a few days where the supplements appear to have stopped working. This is because the body is lowering the amounts of enzymes in response to the sudden increase in SAMe. After 3-8 days a level of balance should occur and if there is improvement but not resolution of symptoms, more of one or more of the supplements may be needed. If resolution has occurred then a gradual lowering of the doses of supplements may be experimented with. The amounts needed are affected by the person's gene mutations as well as environmental factors. I am using this method with two of my sons. I will report on the results when more time has passed, but it looks promising so far. What do you think? Do you see any flaws in my thinking? Is my explanation clear enough? 1. Eur J Pediatr. 1998 Apr;157 Suppl 2:S40-4 The metabolism of homocysteine: pathways and regulation.