My 17 year old son was suffering from fatigue for a year and a half, and I am sure that he would have ended up with either chronic fatigue or ended up with being depressed for the rest of his life if we hadn't made some discoveries. Here is our latest discovery: Magnesium deficiency will cause symptoms of deficiency of the other cofactors of the enzymes that use magnesium, (and there are a lot of those) even if there isn't a deficiency in the cofactor. After extreme fatigue for a year and a half my son started taking 5 mg of methylfolate a day and it was like magic; within 3 hours he felt much better. However, what we have learned lately is that he was actually deficient in magnesium, not folate, and since magnesium is required for the MAT enzyme to transform methionine into SAMe, low magnesium will slow the methionine cycle and thus also slow the folate cycle – leading to symptoms of low folate. (It will also affect the other products dependent on the methylation cycle, such as homocysteine and SAMe levels, and glutathione production, and these have their own set of symptoms.) Unfortunately, you have to be extremely low on magnesium before the deficiency will show up on blood or hair tests, and our experience in our family is that low magnesium will lead to symptoms long before any testing will show it. So our son started taking methylfolate and he was feeling less and less fatigued, but then he started having symptoms of depression. I now realize that by pushing the methylation cycle, I was drawing magnesium away from other enzymes and adding to his problems. (I should mention that he was getting a supplement with about the RDA of magnesium at this time.) The depression got worse as his stores of magnesium were more and more depleted and the enzymes for getting rid of acetaldehyde and histamine were affected, because histamine was what directly caused his depression. I was giving him supplements to support the affected pathways such as niacin, folate, b12 and B6 and later pantothenic acid, but having these pathways running top speed caused a greater need for magnesium that was beyond what his body could absorb, no matter how much I gave him. The answer was to stop all of the B vitamins and keep supplementing magnesium and then his body was able to regulate all his pathways with much less magnesium, and no bowel tolerance, and his symptoms magically went away. (Symptoms caused more indirectly would take more time to go away.) So how did my son become so deficient in magnesium? It all boils down to water supply. There is usually plenty of magnesium in groundwater, but first we lived for 5 years in a house with a water softener, which removes all of the magnesium, and then we lived in a home with a water neutralizer that was using magnesium oxide at first, and there was no problem with that, but then only calcium carbonate was available locally and we put it in with no thought to the fact that we were adding a lot of calcium to our diet, but without magnesium to balance. So there are two morals to this story: Check to see if you are getting magnesium in your water supply, and if you are having trouble with methylation or any other biological pathway in the body that uses magnesium (there are about 300) supplement first with magnesium and then if magnesium alone doesn't do the trick, add other supplements such as B vitamins, because if you are low on magnesium and you push those pathways you will only increase your difficulty in getting enough magnesium without having bowel tolerance and this will lead to problems in other pathways and a myriad of symptoms depending on a person's genetic and environmental factors. I think that magnesium deficiency can show up with a great variety of symptoms and my son didn't show any of the magnesium symptoms that are usually talked about such as muscle spasms or cramps. He has one copy of MTHFR C677T and I guess that is probably why fatigue was his first symptom, because he has a weakness in folate metabolism and low magnesium will slow methylation.