I'm writing this about an idea I had about the beta-3 receptor in CFS. Per wikipedia: Actions of the β3 receptor include Enhancement of lipolysis in adipose tissue. Thermogenesis in skeletal muscle Which doesn't seem particularly important at first. Let me start with OI, many patients with CFS have it. Frequent Urination is a common symptom and led me to Mirabergon, a new drug that acts as a beta3 agonist. It relaxes the bladder basically. But in addition, it was found to raise blood pressure, basal heart rate and metabolic rate which are signs of cardiac stimulation. I also read that beta3 agonist that pass the blood brain barrier can have anti-anxiety and anti-depressive activities. This brought me back to Leptin, which was found to have an inverse relationship with CFS symptoms. It was assumed this was because it primed microglia activity. However, Leptin also attenuates the HPA axis, "leptin was found to dampen the HPA axis response to many kinds of stress" (http://www.nature.com/nrendo/journal/v11/n5/full/nrendo.2015.34.html, https://www.ncbi.nlm.nih.gov/pubmed/17725965). I have seen many people fail, including myself, for any noticeable benefits from microglia inhibition, despite trying many supplements and acknowledging that supplements are only so strong (but should be strong enough based on my research). However, I have also seen many people express improvements from sleep inhibition or food inhibition - which inhibit leptin expression or secretion (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC535701/). In addition to doing the above, Beta3 activation suppresses Leptin expression (https://www.ncbi.nlm.nih.gov/pubmed/8666142) and Leptin secretion (https://www.ncbi.nlm.nih.gov/pubmed/12080443, https://www.ncbi.nlm.nih.gov/pubmed/8756584). It got me thinking if beta 3 tolerance or under activation might contribute to CFS. So, what about the metabolism? In @Hip 's review of Myhills research is noted "in ME/CFS patients, during physical exercise, there is an acute shortage of energy and the mitochondria cannot recycle ADP back to ATP fast enough, so there is a build up of ADP molecules." Myhill notes in her own paper "ECT...regenerates ATP from ADP by the process of oxidative phosphorylation". It just happens, that the thermogenesis activated by the beta 3 receptor is via activation of mitochondrial uncoupling factor 1 - "which mediates a proton conductance pathway that uncouples oxidative phosphorylation," (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508828/, https://www.ncbi.nlm.nih.gov/pubmed/9530130) in fat and slow twitch muscle fibers. I'm far from an expert on the metabolism and mitochondria, and I can't seem to find the specific blocks that Fluge and Mella and Davis identified (2 different ones if anyone remembers feel free to post them), other wise I would try to see if there is a link there. Anyway, I just thought it was interesting. Edit: I did find Fluge and Mella identified pyruvate dehydrogenase inhibition. I couldn't find a link so far, but its possible that some of the activities of b3 act on the kinases which inhibit or activate PD downstream. Also found this w/ regards to calcium ions "Calcium ion has a role in regulation of PDC in muscle tissue, because it activates PDP". PDP activates PD, so maybe the Australian's research can be linked to Fluge & Mellas.