This post is about the possible contribution of ammonia to chronic fatigue syndrome symptoms of anxiety, as well as the well-known "wired but tired" state in CFS. I have high anxiety (generalized anxiety disorder, GAD) as one of my CFS symptoms. I believe anxiety symptoms are found in around 30% of CFS patients, so they are quite common. But even if a CFS patient does not have anxiety, nearly all CFS patients experience the "wired but tired" mental state; and I believe this "wired" state is a kind of low-powered version of the anxiety state. Indeed, on a good day, I merely feel "wired but tired", but on a bad day, when my internal anxiety levels go higher, my mental state swings up into full anxiety. So perhaps everyone with CFS is over-stimulated on the anxiety axis, but just to different degrees. But anyway, that is just a preamble. The question is: what is the anxiety axis, and what biochemical pathways are over-revving it? I think the answer may lie, at least in part, in the NMDA receptors in the brain. It is well-known that the NMDA receptors found on neurons mediate anxiety behavior. Normally, the NMDA receptor is activated by the brain's neurotransmitter glutamate. However, a number of other substances can also activate the NMDA receptor. Thus presumably, any chemical in the body that can stimulate the NMDA receptors, and that can cross the blood-brain barrier, may potentially generate a constant "wired" or high anxiety state. Such anxiety states will be generated irrespective of life circumstances: it is not a psychologically-caused anxiety, but biochemically-generated anxiety — and thus one you cannot directly control. One chemical that is a potent activator of the NMDA receptors is ammonia. Ammonia can be produced in the body by various pathological processes, and it can cross the blood-brain barrier very easily. In particular, many bacteria can produce ammonia. One example is Proteus mirabilis, commonly found in in the gut/kidneys of people with urinary tract infections. Proteus mirabilis produces an enzyme called urease, which converts the urea found in the blood and urine into ammonia. My Genova Diagnostics Comprehensive Digestive Stool Analysis showed that I have high levels of Proteus mirabilis in my gut. I also have a recurrent urinary tract kidney infection, which I speculate may also be caused by Proteus mirabilis. Urease is a virulence factor in UTIs caused by these bacteria. Several other species of bacteria can also manufacture the urease enzyme, which converts urea to ammonia, and thus these bacteria may potentially be creating high ammonia levels in the body. Bacteria which make urease include: MRSA (90% of MRSA strains produce urease), Staphylococcus saprophiticus, Helicobacter pylori, Mycobacterium tuberculosis, Mycobacterium bovis, Proteus vulgaris, Proteus penneri, Nocardia, Brucella, Corynebacterium urealyticum, Morganella, Providencia, Ureaplasma urealyticum, Klebsiella spp, possibly Serratia spp, 2% of Clostridium perfringers strains make urease, 1% of Escherichia coli strains make urease. The fungus Cryptococcus also makes urease. Refs: 1 2 All bacteria possessing the urease enzyme will have the potential to produce ammonia. If ammonia, by activating the NMDA receptor, is contributing to the CFS "wired but tired" symptoms and/or is causing generalized anxiety disorder, one approach to combatting these "wired" and/or anxiety symptoms would be to block NMDA receptor activation. Interestingly, high-dose transdermal magnesium cream — one of the classic CFS palliatives — is a good blocker of NMDA receptor activation. I expect that is why magnesium is a calming supplement in general. Other blockers of NMDA activation (NMDA antagonists) include: taurine, cat's claw (possibly), guaifenesin (possibly) and the drugs: memantine, ketamine, riluzole, dextromethorphan, amantadine, and also more obscure ones: nitrous oxide and ibogaine. Other NMDA antagonists listed here. But rather than just trying to block the NMDA receptor with high-dose magnesium and other NMDA antagonists, another strategy might be to try to stop the ammonia being produced at source (that is, tackling any ammonia-producing bacteria in the gut, kidneys or sinuses), or detoxifying the ammonia in the blood. Ammonia producing bacteria in the gut might be tackled with antibiotics, but a better approach may be to displace them by taking probiotics and prebiotics. In terms of detoxifying ammonia, the following supplements are effective: Ammonia Detoxification Protocol: Ornithine 2 grams Arginine 2 grams Citrulline 2 grams Yucca root 2 grams (Ornithine is contraindicated for anyone with a history of schizophrenia / psychosis). Note that yucca root and yuca (cassava, manioc) are not the same. (Note 1: I read that NMDA receptors are also over-stimulated by the immune system itself, whenever there is an infection within the brain. A part of the brains own immune system, the microglia, rather unfortunately secrete both glutamate and quinolinic acid — both powerful NMDA activators — as a byproduct of their operation. (Not a very clever design). Thus, in as far as CFS is a central nervous system infection, there may already be some NMDA over-stimulation going on, just from the the microglia, even before ammonia might contribute to the act.) (Note 2: Perhaps there are also other NMDA agonists at play, in addition to ammonia, glutamate and quinolinic acid, that further underpin the "wired but tired" or anxiety states of CFS).