Included below is a segment of research I'm compiling into PDF and written format on copper's importance in CFS. This is just a rough look into a particular aspect I'm investigating, the relationship of copper and carnosine. Hope you find something useful. Wilson's Disease; Wilson's disease is a rare hereditary disorder of copper transportation and elimination in the body. "Copper-transporting ATPase 2 is found primarily in the liver, with smaller amounts in the kidneys and brain. It plays a role in the transport of copper from the liver to other parts of the body. Copper is an important part of certain enzymes that maintain normal cell functions. Copper-transporting ATPase 2 is also important for the removal of excess copper from the body." https://ghr.nlm.nih.gov/gene/ATP7B#location ATP7B is the chaperone enzyme that carries copper from the liver, around the body to be used in many extremely important functions. These include neurotransmitter production, ATP production, white blood cell formation, anti-inflammatory response activation, anti-histamine function, muscle development and maintenance, immune system response, central nervous system communication etc. etc. "The majority of these mutations are clustered in the transmembrane domains of the encoded protein. In Europeans and North Americans two mutations account for 38% of the observed mutations in this disease. These two mutations are a substitution of glutamine for histidine at amino acid 1069 (H1069Q) and arginine for glycine at amino acid 1267 (G1267R)." https://themedicalbiochemistrypage.org/wilsondisease.php In Wilson's disease an inability to properly utilize, transport and remove copper occurs. This results in both a copper deficiency and copper toxicity. Seeing an increase in aceruloplasmin and unbound (free) copper a buildup of hepatic, kidney and brain copper occurs. Resulting in kidney dysfunction and failure, hepatic dysfunction and failure and severe cognitive defects, particularly involving emotional regulation. "Overmethylation "Overmethylation is the polar opposite of undermethylation. If you are overmethylated, you will likely have elevated levels of serotonin, low levels of histamine, and likely a low count of absolute basophils. Additionally you may discover high levels of copper, but low presence of zinc and histamine throughout the body." http://mentalhealthdaily.com/2015/0...s-overmethylation-causes-symptoms-treatments/ Although this is a gross oversimplification of methylation status in humans, it can be used as a guideline, particularly in reference to copper and histamine status in the body, or more accurately their inverse nature to one another. While research on the internet is all over the place in regards to copper status relative to histamine levels in the blood, this is due to a misconception of what high serum and hair copper levels actually mean. A high level of serum copper is not an indicator of high dietary copper, as I will touch on shortly. A high level of copper in the blood is in all cases but acute copper poisoning, an indicator of one of three things. 1) Impaired copper transport, or weak digestion or metabolism of copper 2) A biomarker of infection, and a myriad of illness' 3) Malfunctioning or inadequate levels of SOD2 (MnSOD) Impaired copper transport Contrary to government claims of nutritional copper adequacy generally occurring from drinking water alone coming from up to 6.0mg/L of tap water, this is a completely baseless and false argument. If anything the copper in drinking water will deplete copper rapidly, and does not act as biologically available copper does. The copper you will find in pipes is free copper, this should be considered a poison, not a supplemental source of copper in the diet. Free copper is not chaperoned to the necessary copper dependent enzymes as biological copper from ATP7B would be, it has already been oxidized and will serve only to cause free radical damage in the body at copper dependent locations, causing overactive and malfunctioning enzymatic reactions. This overloads the body with free copper that needs to be removed from the body, this will bind up ceruloplasmin making it unavailable in the transport of bioavailable copper, leading to decreased levels of ceruloplasmin, bioavailable copper, copper dependent enzymatic function, and eventually a rise to kidney dysfunction, endocrine disruption, and ever increasing levels of epinepherine. The body's main superoxide scavenger, SOD1 (CuZnSOD) a copper dependent antioxidant, will be unavailable to prevent or mitigate damage caused by oxidized free copper in drinking water. This leads to another confusing myth regarding an apparent "excess or abundance" of copper in our diet. Our food. It has been asserted many times that a vegetarian diet will contain too much copper compared to an omnivorous or carnivorous diet. This has had me scratching my head for quite some time. Let's get into the basic facts first. Zinc competes with copper "Zinc produces a mucosal block by inducing metallothionein, which binds copper in mucosal cells until they slough off and are eliminated in the feces. and it competes with copper for absorption in the intestine by DMT1 (Divalent Metal transporter 1)." https://en.wikipedia.org/wiki/Copper_in_health Zinc will compete heavily with copper in the digestive process, preventing the absorption of copper, binding it to (MT) bringing it out of the body. I will list a few examples of the best vegetarian sources of copper, that are generally avoided heavily by those concerned with copper toxicity. Spinach, not the greatest source, but the most touted as being one. 0.4mg of Copper per 10oz (over half a pound of raw spinach) 1.5mg of Zinc per 10oz The RDA for copper is set at 2mg/day, the UL is set at 10mg with no significant risk to healthy individuals. If one were copper deficient this RDA simply is far too low, it would be impossible to reverse a copper deficiency with a level this low. I don't know of many people who consume around 3.1lbs of raw spinach a day. But that would be the requirement to hit adequate status. Besides this, the human body can only absorb 30-40% of dietary copper. https://www.ncbi.nlm.nih.gov/pubmed/9587151 Pair this with around a four fold zinc to copper ratio, and you're looking at a minimum of 7lbs of raw spinach a day to meet the RDA. Because of the copper toxicity paranoia, the government has endorsed the use of glyophosphate as a means of chelating copper complexes (in this particular case, copper sulphate which has been demonstrated to act in an antagonistic manner to many copper dependent enzymes in an unknown manner), the use of bioavailable copper in soil has decreased to prevent this nightmare of copper toxicity, and glyophosphate is being used on at least 30% of crops. Glyophosphate binds and inactivates any copper that would be bioavailable within the plant, and increases yield. Put all this together and you could make the assumption that the predicted 0.4mg of copper per 10oz of spinach is quite a bit lower, though I'm not one to jump to conclusions, there have been no adequate studies done into the current level of copper in our crops. https://www.ncbi.nlm.nih.gov/pubmed/23733011 Let's look at the greatest source of copper in vegetarian foods. Sesame seeds 1.47mg of copper per 1/4 cup 2.79mg of zinc per 1/4 cup Now this is more like it. We generally see people aiming for a 7-14x Zinc to Copper ratio, depending on who's pushing it. But as far as the science goes, there isn't enough zinc in Sesame seeds to nearly or completely prevent the absorption of copper as you will find in any of the other "top sources" of copper in food. Copper should always be taken away from Zinc to prevent this block in absorption, I've heard it claimed everywhere that vegetarians eat food that is too high in copper and too low in Zinc, but I can't for the life of me find a case where Zinc is not in favor, or heavily in favor. Or where copper content is in any way adequate or will make any contribution to maintaining or restoring proper copper levels in the body. Now let's look at meat eaters, you'll find many accounts of ex-vegetarians who became massively copper toxic who switched back to meat who found a dramatic reduction in their copper toxic symptoms. Why this isn't seen as treating a long standing copper deficiency is beyond me. First, the greatest source of copper in diet for humans. Beef liver An 100 gram portion of beef liver contains 12mg of copper and 4mg of zinc Red meat also contains the largest amount of carnosine in food, more on the importance of carnosine to come, as it ties into the center point of this investigation. Considering the RDA at 0.9 to 2.0mg of copper it seems strange that many very healthy people eat liver multiple times per week and aren't succumbing to copper toxicity. For vegetarians to mitigate this is very simple, Shitake Mushrooms are an excellent source of copper and because of the way they are grown, you don't have to be too concerned about copper depletion or pesticide use. The basic idea I'm trying to get across is that we have very little copper coming in through diet, factoring in the heavy intake of processed foods, high amounts of zinc and high sugar foods, we can safely say that avoiding a functional copper deficiency is all but impossible without supplementation. There was a time when our crops were allowed to grow naturally, and contained similar nutrient profiles to what our ancestors were used to (evolution doesn't work as quickly as it seems people assume it does, if you're a theist disregard this, I am not being political and not trying to pigeon hole anyone, if you are a theist just consider the difference between what humans were consuming 2000 years ago to now, and how much more processed and contaminated our food has become, the logic fits either side and I am encouraging health and wellness, not atheism). Elevated copper in serum as a biomarker of illness or infection Copper is required for the immune system to function, it supports the thyroid, the pancreas, the entire endocrine system, cell division, hemoglobin synthesis, iron utilization, white blood cells, a healthy digestive tract, kidney and liver function, brain health, ATP production, free radical scavenging, anti oxidant systems and a healthy heart. It is also essential for a functioning central nervous system. In times of stress, infection or any immunosupressive activity in the body, copper is released to required sites at the body to stave of infection, in the case of heavy metal toxicity where mercury, lead, cadmium etc. are at high levels in the body, they will take up free metallotheine and ceruloplasmin, preventing the previously released copper from being rebound and brought back out of the body after it's oxidization. This oxidized copper rampages through the body causing in many cases more damage than it mitigated in the first place, this high level of serum copper leads to increasingly worsened absorption of copper, damage to the gastrointestinal system and impairment of ceruloplasmin production. Copper is eventually shuttled to the liver, kidneys and brain in it's oxidized form and remains there to prevent any further free radical damage in the body, this leads to toxic levels of copper in the tissue, indicating an excess of copper which is always seen as too much dietary copper, but as we looked into earlier, where is this excess dietary copper coming from? What seems to be overlooked is that copper will not reach toxic levels in the body unless ceruloplasmin or metallotheine have been impaired, or in cases of acute copper poisoning, which are invariably intentional suicidal acts. Now how can it be that one could be in a stage of inadequate ceruloplasmin? Could the avoidance of copper have anything to do with it? Ceruloplasmin requires copper to be manufactured, if we aren't consuming copper where is it coming from? After long standing illness, and years of copper toxicity, most functions requiring copper have been shut off, similar to how long standing folate and b12 deficiencies will impair methylation. At this point, you've probably been sick most of your life, barely able to remember a time when you were healthy, most of your endocrine system is non functional, your neurotransmitter production is impaired to the point of serious depression or mental illness, your liver and kidneys having been poisoned by oxidized copper for years are greatly impaired, and correcting a deficiency in most cases is going to make you much worse. Similar to refeeding syndrome, reactivating long dormant copper dependant enzymatic function will cause a severe worsening of your condition, the immune system will kick in not realizing it's been almost impossibly outnumbered by heavy metals, infection and lymph node storage of toxins which will be released to be processed, heavy metal build up which continued unchecked in the absence of adequate (MT) and (Cp) and you are now in a state very similar to hereditary Wilson's disease, symptomatically at the very least. At this point taking the necessary levels of copper to re-establish proper functioning of the endocrine and immune system becomes impossible, there is not enough ceruloplasmin production to maintain and remove the amounts of copper necessary to get better, worse yet, because of the binding affinity for (Cp) and (MT) heavy metals will cause an overload leading to increased free copper buildup in the body, you manufacture the resources needed to pull copper out, but too much copper is needed in the body, so is released, and because of the drastically increased levels of free radicals, ends up becoming oxidized in it's SOD functioning. This increases stress and ACTH dramatically, and the liver cannot keep up with ATP7B production, it cannot keep up with ceruloplasmin production, and it cannot keep up with toxin removal, you get worse, and obviously the first thing that comes to mind is that this copper is making you sick, copper must be poison, so you start taking massive doses of vitamin C (which requires copper to function outside of copper chelation), you start taking heavy amounts of molybdenum and zinc, and your bioavailable copper goes even lower, at this point any copper you take in becomes oxidized free copper, making things worse, and worse. You go and get blood tests, they turn up fine, Doctors are at a loss, or think you're making everything up, CFS isn't real etc, etc. You're stuck in an endless loop of protocol after protocol, most of which antagonize copper and vilify copper as being the root cause. Every now and then you restore function to one apparatus to have two more fail, you have a few good days followed by months of the same old chronic illness. You try every diet known to man, nothing helps, you're still sick. How many "protocols" do you follow? How many gurus do you chase after, throwing your money at them to save you from the misery you find yourself in? If you look at standard treatment for WIlson's disease, these people don't get "better" in any real way, they see a dramatic decrease in many symptoms, but still continue to be prone to chronic fatigue, depression, illness etc. The standard treatment for Wilson's is basically the same for alternative health issues in general, avoid copper at all costs, and chelate the hell out of it. So what about your neurotransmitter production? What about your endocrine system, or immune system? Do we not need them? This brings me to a very important connection to the idea of overmethylation earlier, high copper, low histamine. And I don't want this to put those who have histamine intolerance off, or even those who are undermethylators (which would have to be rare on a forum dedicated to people with severe folate/B12 issues who lack energy and motivation) , there is a connection here as well for you. Copper is required for the functioning of the enzyme DAO (Diamine Oxidase), this is a copper dependent enzyme that breaks down histamine, in the presence of greater amounts of copper, greater amounts of histamine will be broken down. Now, you're never going to be fully certain of which enzymes free copper is in binding capacity with, which is why copper toxicity doesn't always show the exact same symptoms, or why any diseases doesn't, we're all unique and have different genes and diet, and live different lifestyles. What happens when excessive amounts of copper are released to drive DAO enzyme function, lowering histamine dramatically, but that copper remains a free radical, not being pulled out of the body? Your histamine ends up being tanked by DAO, your bioavailable copper is non existent, and you manage to get a good deal of your bio-unavailable copper out without ceruloplasmin? Well, unbound copper and histamine work inversely to one another, and you end up in a situation where you don't have bioavailable copper to produce DAO, but managed to remove enough bio-unavailable copper to allow histamine to rise, lacking the necessary cofactor of Copper to allow DAO functioning, histamine gets out of control. There is an incredibly huge difference between L-Histidine and Histamine in the body, many assume that consuming L-Histidine as it is a precursor to Histamine will do that, and only that. As the centerpiece and hallmark of this write up, Histidine is examined as both a way to maintain adequate copper levels in the body, copper dependent enzymatic function in the body and to remove oxidized and bio-unavailable copper molecules from the body simultaneously bypassing the need for adequate ceruloplasmin production and ATP7B functioning in the body. Returning the body back to it's homeostasis. Rather than supplementing copper and in most cases getting worse, overloading the body. Or chelating copper, and becoming worse due to non-selective affinity for what forms of copper are chelated and removed (I'm looking at penecillimine here, and the terrible neurological outcomes of this treatment in Wilson's). L-Histidine seems to almost be too good to be true. Histidine itself is required for the functions of most minerals in the body, without adequate stores they are usually left to become oxidized and cause tremendous amounts of damage to the body. CuZnSOD requires Histidine to be manufactured, (MT) requires Histidine, Iron, Molybdenum, Selenium, Zinc, Copper all require Histidine to function biologically. Histidine forms CuZnSOD and 3) MnFeSOD (without adequate functioning of MnSOD or proper levels of manganese, mitochondria will be damaged by superoxide, this will leak out of the cells and force CuZnSOD into production, further reducing bioavailable copper in an attempt to mitigate damage outside of the mitochondria. Histidine is also required to produce Cysteine Dioxygenase, do you have a cysteine problem? Because of the half life of Histidine being 6 minutes, and the fact that it is capable of binding to heavy metals, the issue of redistribution appears. But this is completely offset through another means of supplementation as I will get to. Histidine is able to form five complexes with copper. This is through Hisidine anion (L-) and the Zwitterion (HL+-) allowing it to either freely exchange through albumin or both shuttle bio-available copper around the body to necessary locations and to complex free copper to bring it out of the body, this function is presently unknown, bypassing the need on ceruloplasmin, reducing the load to either allow (MT) and (Cp) to heal and regenerate, or to be used in binding up other heavy metals. These complexes are CuL+, CuHL++, CuL2, CuHL2+ and Cu(HL)2++, these are dependent on blood pH. https://www.nature.com/nature/journal/v184/n4702/abs/1841868a0.html As I mentioned earlier, a need to bypass the short halflife and inadequacy of Histidine is required, and we have just the compound. It will act as an intelligent storage and release. And on it's own has amazing properties I will discuss. Carnosine is a combination of Histidine and Beta-Alanine. The carnosinase enzyme breaks carnosine down to Histidine and Alanine to be used in the body. The only reliable and quality study done into Carnosine on humans was in autistic children, this study showed no long term benefit. What really gets me about this study, is that there was no low, medium or high dose groups. It was just 800mg/day. They could have just given the kids alanine and histidine and called it a day, while carnosine has a half life in the body of 6 hours, it is readily broken down by the enzyme carnosinase into it's respective components. In order for carnosine to create a steady and reliable flow of histidine and alanine into the blood, the carnosinase enzyme must be overloaded, and additional carnosine added to the diet to create a surplus. The minimum required dose to do this seems to be about 1G, that doesn't include the additional carnosine required afterwards to create a surplus. So it's not really any surprise that their trial had no effect, they used a modest dosage that did not allow for the inhibition of carnosinase to allow a store to be made. Carnosine on it's own is an incredible antioxidant, acting as a cell buffer for metal transition oxidative damage, reducing the transition of Fe(III) to Fe(II), protecting deoxyribose from oxidation by Fe(II), Fe(III) and Cu(II). It has the ability to form its own SOD complex with copper in the body acting as both a copper chelator and superoxide scavenger with the copper it has chelated, that not only acts in a similar manner to CuZnSOD but also acts remarkably as an SOD on DNA. When allowed to build a store of carnosine, the body will provide itself with an ability to keep copper going where it needs to go and from oxidizing and ending up stuck in the body, and will chelate excess copper using it to prevent superoxide damage on the way out. The antioxidant effects of carnosine are of particular interest to those with MAO-A and MAO-B excess, as this will cause oxidative stress to both the serotenergic and dopaminergic systems further aggravating your problem. Carnosine itself also acts as a potent MAOB inhibitor and a very potent DBH inhibitor (an overload of copper turning all available dopamine into norepinepherine and an overactive methylation cycle breaking that further down to epinepherine, lack of joy/motivation/calm anyone?) Anyways this about wraps up my rough look into the relationship between copper and carnosine. I'm currently doing a pretty substantial research project on this and will be turning this into an e-book PDF format, this write up does not reflect the quality I am aiming for, I just find Carnosine to be too remarkable in the treatment of copper toxicity and deficiency to hold onto, I wanted to get this rough draft out quickly but it will be part of my PDF e-book in the future, obviously cleaned up substantially. If you would like to get started on your own research into Carnosine, I'd suggest https://selfhacked.com/blog/carnosine/ as an introduction. Thanks for your time, I hope it's of some interest to any of you dealing with chronic copper issues.