This post is about the possible contribution of ammonia to chronic fatigue syndrome symptoms of anxiety, and the well-known "wired but tired" mental 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 pathway(s) 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 stimulated (switched on) by the brain's neurotransmitter glutamate. However, a number of other substances can also switch on the NMDA receptor. Presumably, any foreign chemical substance in the body that can stimulate the NMDA receptors, and that can cross the blood-brain barrier, will potentially generate a constant "wired" or high anxiety state. Such anxiety states will be generated irrespective of life circumstances: it is not a normal psychologically-produced anxiety, but biochemically-generated anxiety - and thus one you cannot directly control. Now, one chemical substance 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. 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 urea into ammonia. (Incidentally, Proteus mirabilis is also a sulfur-reducing bacterium that can produce H2S). There are other species of bacteria that can also produce urease, and so may potentially produce ammonia. So I wonder if there is another gut/kidney - brain connection in CFS, via ammonia produced in the gut or kidenys, that underpins the "wired but tired" and anxiety states of CFS. Interestingly, high-dose magnesium - 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: zinc, taurine, progesterone, cats's claw (possibly), guaifenesin (possibly) and the drugs: memantine, ketamine, riluzole, dextromethorphan, amantadine, and also more obscure ones: nitrous oxide, xenon gas, and ibogaine. As many CFS patients can testify, these supplement can all help in reducing the "wired but tired"/anxiety state. The mental tiredness may arise, in part, from the NMDA overestimation itself, which exhausts the brain cells (and can cause brain cell death by excitotoxicity). But if ammonia is contributing to CFS symptoms (a big if), then rather than just trying to block the NMDA receptor with magnesium etc, perhaps there might be ways of stopping ammonia being produced at source (that is, tackling any ammonia-producing bacteria in the gut, kidneys, or perhaps even sinuses). (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).