I'm just a person with no qualifications so don't take this theory too seriously, it is mostly speculation. Studies have shown that TRP channels may be related to CFS: Interpretation: Certain TRP SNP mutations are associated with CFS. Usually mutations hamper effectiveness. Secondly TRPM3 surface expression was significantly reduced on certain immune cells. They did not test to see if TRPM3 is poorly expressed in many different cells, only immune cells. They also didn't check levels of other cations such as magnesium, zinc etc. Relevant info from the web on TRP channels: TRPM3, TRPM6 and TRPM7 are highly permeable to both calcium and magnesium. These channels are also permiable to other cations, such as zinc, even more so than calcium and magnesium. Spoiler TrpM6/7 TrpM7 was the first among Trp channels found to be Zn2+ permeable . TrpM6/7 are unique among channels because they also possess a kinase domain [117, 118]. TrpM7 plays a key role in intracellular Mg2+ homeostasis and in neuronal Ca2+ toxicity in ischemic conditions [118-122]. Monteilh-Zoller et al. demonstrated that the permeability of TrpM7 channels for Zn2+ ions is four-fold higher compared to Ca2+ . TrpM7-overexpressing cells showed intracellular Zn2+accumulation as indicated by increased fluorescence of FluoZin-3, a recently developed Zn2+fluorescent indicator . This Zn2+ accumulation contributes to, at least in part, functional gene expression in neuronal cells through the activation of metal-responsive element, which is important for monitoring intracellular metal levels [123-125]. Thus, not only because of abnormal cellular function (see above), but also because of changes in various gene expression, Zn2+ overload through TrpM7 will facilitate cytotoxicity [123, 126]. TrpM6, a homolog of TrpM7, also has a kinase domain. It has been implicated in Mg2+ homeostasis in the intestines and kidneys [120, 127]. Similar to TrpM7, TrpM6 has also been shown to be Zn2+ permeable . TrpM3 TrpM3, a member of TRP channels highly expressed in brain and in pancreatic β cells [129,130], is important for insulin release . Zn2+ has been found in the vesicles of these cells, which is co-released with insulin and contributes to insulin function [131, 132]. While ZnT8 was speculated to facilitate Zn2+ uptake from cytoplasm into vesicles , Zn2+ permeability has recently been shown in one of the TrpM3 variants in native pancreatic β cells . TrpM3 appears to contribute to Zn2+ permeation comparable to VDCCs . Since activation of TrpM3 produces depolarization of β cells, which can lead to additional Zn2+ influx through VDCCs, further segregation of functional significance of Zn2+ entry between TrpM3 and VDCCs may be explored in the near future. TRPM6 and 7 are dependant on ATP. "TRPM6 and TRPM7, for example, contain functional α-kinase segments" and "The kinase activity is necessary for channel function, as shown by its dependence on intracellular ATP and by the kinase mutants." ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. Defects in TRPM7 have been associated to magnesium deficiency in human microvascular endothelial cells. Defects in TRPM6 are associated with hypomagnesemia with secondary hypocalcemia. People with CFS have low red blood cell magnesium. Vagus nerve also has many TRP channels. Theory: TRPM6 and 7 are hampered by extremely low ATP, while TRPM3 is barely working from DNA mutations and low gene expression. This leads to low levels of intracellular cations such as magnesium, zinc, copper, calcium, manganese. Any ATP that is produced is not bio-available because it is not bound to magnesium. TRPM6/7 never activate because of low ATP Methylation cycle stops working because of low intracellular zinc, copper, and magnesium. (essential cofactors for methylation) Neurotransmitter production is impaired through poor methylation. Neurotransmitter release is impaired because calcium is needed to release neurotransmitters from vesicles. Viruses proliferate because of impaired DNA repair and low glutathione. Those processes are dependent on methylation. The initial trigger of CFS would be ATP depletion, due to repetitive stress, bad viral infections, etc. This wouldn't show up like normal zinc, magnesium etc deficiency because only certain cells are dependent on TRPM channels for cation transport, and even then they probably have a few backup mechanisms, so the deficiency is there but not as severe as it could be. It is also possible that the ATP depletion is only in certain muscles/nerves. Most people do not get CFS because TRPM3 doesn't require ATP to function, and so even if there is low ATP, there can still be high Zinc/Magnesium etc. In the second study listed near the top of this post, it shows that there was a significant reduction in intracellular calcium levels due to low amounts of TRPM3. Through this, we can infer that the dysfunction in cation transport is somewhat significant. Trigger points may occur when the ATP depletion and TRP6/7 magnesium lock is even more intense. My personal experience which was used to help come up with this theory: Spoiler A few times I've been able to get complete remittance of my CFS with PEMF + Wim Hoff style breathing + Resveratrol + low dose Aspirin + large amounts of magnesium (like 3g), zinc (300mg), copper(15 mg), manganese(50mg). PEMF has been hailed by the owner of selfhacked as the best cure to his fatigue. I am guessing it increases ATP production through some mechanism. Basically I take these supplements, lie in bed, and do the breathing while using the PEMF. I breath heavily until I get dizzy, stop until I feel the urge to breath again (signalling that CO2 is raised back to normal levels), then repeat. During this process and afterwards, I can take and absorb massive amounts of magnesium etc without getting diarrhea or side effects. Slowly my symptoms start to improve. Normally I can only tolerate 400 mg of magnesium. I believe the breathing + PEMF process helps with oxygenation and jump starts atp production. This then activates TRP6/7 and increases mineral absorption. One time I did this, and got my best result. I was symptom free for 2 days, and had so much neurotransmitters it was like I was on phenibut + adderall + mdma or something. I had unbelievable energy like my body was a furnace. It was like there was a force pushing my back and every movement and thought was effortless. This wasn't mania, I experienced mania before and I know how to recognize it. I even had thoughts of going over and talking to strangers, getting a girlfriend etc, it was amazing. I also had a near-photographic memory and was very verbally fluent. Then after those 2 days ended, I must have had ATP depletion or viral reactivation or something, and I had diarrhea all night, excreting that 3g of magnesium and my symptoms all came back. Sadly this process is hard to replicate and keep, I think because it is hard to get the ATP levels started and stay high. Secondly the side effects when the process fails to keep going are fairly bad, diarrhea all day ><. And then that messes up my microbiome and gut health. Also I cannot keep trying to replicate this often because of potential copper/manganese/zinc toxicity. EDIT: It is also possible that PEMF stimulated production of some steroid hormones which are known to activate TRPM3. Then I could absorb magnesium etc. Things which need testing according to this theory: Cation levels of different cells in people who have TRPM3 mutations and CFS Note that a test for these TRP mutations is already in the works by the same people who did that Australian study: http://www.sciencealert.com/a-screening-test-for-chronic-fatigue-syndrome-is-ready-for-the-public TLDR: TRPM3 receptor dysfunction leads to low intracellular zinc, magnesium, copper etc, leads to poor ATP bioavailabilty and poor methylation. And some other stuff.