I posted about 8 or 9 months ago about how I was giving certain vitamins to my sons, who have depression and schizophrenia. I have now completely revised my ideas about what is causing their problems, and I think it might be involved in the cause of many other illnesses, including chronic fatigue. I had mentioned once how my son with depression, who I will call D, had experienced extreme fatigue for over a year until we started giving him high doses of methylfolate. Then over a period of several months he became depressed. My son with schizophrenia responded well for about 4-6 weeks to the supplements, and then he relapsed. I have finally figured out why he relapsed. I have a partially new paradigm about how these illnesses are caused. I think I have found one piece of the puzzle that pulls together many other pieces of the puzzle into one comprehensible whole, if I am right in my ideas. This is rather technical, but I know that a lot of you have studied the TCA cycle and I saw there was a good thread about the problems with low sulfate earlier in the year, and this relates to that. I have written a somewhat more scholarly paper about this that I am still revising that has citations if anyone wants to see it. So here is my hypothesis, I have put the most relevant statements in bold so that people who don’t want to wade through the whole thing can just read the bold parts. Human Endogenous Retrovirus (HERV) can be activated by various stressors. In the case of my two sons, they both had mono at the time their illnesses started, and I believe that EBV activated the HERV. I have come to the conclusion that this retrovirus inhibits either sulfite oxidase itself, or the molybdenum cofactor, either of which will raise the sulfite/sulfate ratio. The high sulfite/sulfate ratio can interfere with many processes in the body, including but not limited to sulfation, phenol sulfur-transferase and enzymes which use sulfate as a cofactor, such as aconitase, one of the enzymes in the TCA (citric acid) cycle. There are so many enzymes which are affected by sulfur in the body and many of them could be candidate for inhibition by a high sulfite/sulfate level, directly or indirectly. Which symptoms a person has depends on environmental and genetic factors of the individual. A high cysteine/sulfate ratio has been found in many chronic illnesses, such as CFS, migraine headaches, multiple sclerosis, depression and fibromyalgia (Moss and Waring,"The Plasma Cysteine/Sulphate Ratio: A Possible ClinicalBiomarker" This is a great article and the PDF is available online). I think that this high cystine/sulfate ratio is caused by inhibition of sulfite oxidase. Sulfite oxidase is in the mitochondria and interacts with cytochrome c in the the electron transport chain, part of the energy producing pathways in the mitochondria, which depends on iron-sulfur clusters for electron transport, is inhibited. Since folate is involved in the synthesis or repair of iron-sulfur clusters, large doses of folate improve the function of the electron transport chain, leading to less fatigue in people who are experiencing fatigue due to inhibition of the iron-sulfur clusters in the electron transport chain. The electron transport chain (ETC) takes the H (proton) off of NADH, returning it to NAD. If the electron transport chain is inhibited, NADH can build up in the mitochondrial matrix, leading to inhibition of the alpha-ketoglutarate dehydrogenase enzyme, which changes alpha-ketoglutarate into succinyl-CoA, and truncates, or shortens, the TCA cycle. These low levels of succinyl-CoA are a huge problem, which I will explain below. The TCA cycle enzymes are activated by low ATP, the energy unit of the body, so when a person has fatigue from low ATP, the low ATP overcomes the NADH inhibition and the full TCA cycle creates sufficient succinyl-CoA. Succinyl-CoA is combined in a reaction with glycine, an amino acid, as part of the process of making heme. Heme is required for complex IV in the ETC, and also for sulfite oxidase. Heme is also required to make catalase, an enzyme which changes hydrogen peroxide (H2O2) to O2 and water. High H2O2 can cause many problems: it is involved in signaling the release of dopamine, and it produces free radicals. Catalase is also needed for the dopamine beta-hydroxylase reaction which changes dopamine to norepinephrine. Dopamine beta-hydroxylase has been found to lose more than 90% of its activity without catalase. This can lead to high dopamine and low norepinephrine, causing depression in some people. This is why while D had great fatigue he was not depressed, and when folate made his fatigue go away, he became depressed after his reserves of nor-epinephrine became depleted. We have found that the pyruvate dehydrogenase complex, which changes pyruvate into acetyl CoA to feed into the TCA cycle, is affected, because taking coconut oil, which produces ketones for acetyl CoA production to bypass this enzyme helps relieve symptoms, until molybdenum levels are depleted. We have found that supplementing to bypass these problems drains molybdenum. When we tested our son who has schizophrenia, who I will call S, his RBC molybdenum levels were extremely low after he had relapsed. It is interesting to note that D’s levels were somewhat high, but he didn’t get permanent improvement until we started giving him molybdenum every day. I guess that there is a constant turnover of sulfite oxidase that drains the molybdenum or requires high molybdenum levels to partially overcome the effects of the inhibition when you are taking supplements to keep the TCA cycle moving when sulfite oxidase is inhibited in this way. But molybdenum alone does not fix the problem. Niacin or niacinamide (B3) is required in large doses (250-1000 mg 3X a day) in order for the body to make enough NAD to lower the NADH/NAD ratio and lower inhibition of alpha-ketoglutarate dehydrogenase. This is just my hypothesis, I am not saying that there are studies to prove it. But I can say that this protocol absolutely does not work without the high B3. We have found that B6 is also required. If someone has problems taking B6, they may find that they tolerate it better when they have sufficient B3 and folate (3-5 mg per day) to support these inhibited enzymes. We make coconut treats out of coconut oil, vanilla, ripe banana, cocoa or carob powder and rolled oats to make taking coconut oil easy. Taking doses of 4-8 grams of glycine can help. Glycine does not readily cross the BBB but some of it does when you take large doses. Glycine will help make heme and catalase. R-lipoic acid and CoQ10 might also help some people. Lipoic acid is a cofactor for two of the TCA cycle enzymes and CoQ10 is in the ETC. Calcium and magnesium both have to be sufficient. If you supplement a large amount of one without the other you can run into problems. I am sure other enzymes are affected, but taking these supplements should help with those, too. A lot of this applies to heavy metals toxicity because they affect sulfur enzymes. I hope this is helpful. I know it is pretty confusing but hopefully you get the idea.