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Acetylcholine
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===Chronic fatigue syndrome=== Since at least the 1990s it has been theorized that CFS might be associated with abnormalities of acetylcholine neurotransmission. To test this hypothesis, a provocation study was performed using the acetylcholinesterase inhibitor [[pyridostigmine]]. The results did indicate that CFS patients' hypothalamuses are hypersensitive to cholinergic stimulation relative to matched healthy controls. <ref>{{Cite journal | last = Chaudhuri | first = A. | last2 = Majeed | first2 = T. | last3 = Dinan | first3 = T. | last4 = Behan | first4 = P.O. | date = Jan 1997 | title = Chronic Fatigue Syndrome: A Disorder of Central Cholinergic Transmission | url =http://www.tandfonline.com/doi/full/10.1300/J092v03n01_02 | journal = Journal of Chronic Fatigue Syndrome|language=en | volume = 3 | issue = 1 | pages = 3β16|doi=10.1300/J092v03n01_02|issn=1057-3321}}</ref> These results mirror similar, highly replicated findings showing that CFS patients' hypothalamuses are hypersensitive to serotonergic stimulation as well (see [[Buspirone challenge test]]). A 2003 study of 60 CFS patients found that 53.3% had detectable autoantibodies against the M1 muscarinic acetylcholine receptor. <ref>{{Cite journal | last = Tanaka | first = Susumu | last2 = Kuratsune | first2 = Hirohiko | last3 = Hidaka | first3 = Yoh | last4 = Hakariya | first4 = Yukiko | last5 = Tatsumi | first5 = Ke-Ita | last6 = Takano | first6 = Toru | last7 = Kanakura | first7 = Yuzuru | last8 = Amino | first8 = Nobuyuki | date = 2003-08-01 | title = Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome | url =http://www.spandidos-publications.com/10.3892/ijmm.12.2.225 | journal = International Journal of Molecular Medicine|doi=10.3892/ijmm.12.2.225|issn=1107-3756}}</ref> In 2015, a large German study found 29% of [[ME/CFS]] patients had elevated autoantibodies to M3 and M4 [[muscarinic acetylcholine receptor]]s, as well as Γ2 [[adrenergic receptor]]s.<ref>{{Cite journal | last = Loebel | first = Madlen | last2 = Grabowski | first2 = Patricia | last3 = Heidecke | first3 = Harald | last4 = Bauer | first4 = Sandra | last5 = Hanitsch | first5 = Leif G. | last6 = Wittke | first6 = Kirsten | last7 = Meisel | first7 = Christian | last8 = Reinke | first8 = Petra | last9 = Volk | first9 = Hans-Dieter | date = Feb 2016 | title = Antibodies to Ξ² adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/26399744 | journal = Brain, Behavior, and Immunity | volume = 52 | pages = 32β39|doi=10.1016/j.bbi.2015.09.013|issn=1090-2139|pmid=26399744}}</ref><ref>{{Cite web | url = http://www.meaction.net/2015/09/26/antibodies-found-in-subset-of-cfs-patients/ | title = Autoantibodies found in subset of CFS patients {{!}} #MEAction|website = [[The MEAction Network]]|language=en-US | access-date = 2018-08-10}}</ref> A 2016 Australian study found that ME/CFS patients had significantly greater numbers of [[single nucleotide polymorphism]]s associated with the gene encoding for M3 muscarinic acetylcholine receptors.<ref>{{Cite journal | last = Marshall-Gradisnik | first = Sonya | last2 = Smith | first2 = Peter | last3 = Nilius | first3 = Bernd | last4 = Staines | first4 = Donald R. | date = 2015-01-01 | title = Examination of Single Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrome Patients |url =https://doi.org/10.4137/III.S25105 | journal = Immunology and Immunogenetics Insights|language=en | volume = 7| pages=III.S25105|doi=10.4137/III.S25105|issn=1178-6345}}</ref> Several small clinical trials have been performed to assess the benefit of treatment with acetylcholinesterase inhibitors in CFS; one using pyridostigmine <ref>{{Cite journal | last = Kawamura | first = Yasuo | last2 = Kihara | first2 = Mikihiro | last3 = Nishimoto | first3 = Kazuhiro | last4 = Taki | first4 = Mayumi | date = May 2003 | title = Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports |url =https://linkinghub.elsevier.com/retrieve/pii/S0928468003000075 | journal = Pathophysiology|language=en | volume = 9 | issue = 3 | pages = 189β194|doi=10.1016/S0928-4680(03)00007-5}}</ref> and another using galantamine. <ref>{{Cite journal | last = Snorrason | first = Ernir | last2 = Geirsson | first2 = Arni | last3 = Stefansson | first3 = Kari | date = Jan 1996 | title = Trial of a Selective Acetylcholinesterase Inhibitor, Galanthamine Hydrobromide, in the Treatment of Chronic Fatigue Syndrome | url =http://www.tandfonline.com/doi/full/10.1300/J092v02n02_04 | journal = Journal of Chronic Fatigue Syndrome|language=en | volume = 2 | issue = 2-3 | pages = 35β54|doi=10.1300/J092v02n02_04|issn=1057-3321}}</ref> Both trials showed improvement of symptoms on the treatment. The exact mechanism or mechanisms by which AChE inhibition might help in CFS are unclear due to how widely represented acetylcholine-responsive tissues are in the brain, (neuro)musculature, cranial and pre-ganglionic spinal autonomic nerves, vasculature, and peripheral C-fibers. Additionally, AChE inhibitors such as [[pyridostigmine]] are able to stimulate growth hormone secretion, and both CFS and POTS patients have been shown to have disturbed growth hormone levels. <ref>{{Cite journal | last = Berwaerts | first = J. | last2 = Moorkens | first2 = G. | last3 = Abs | first3 = R. | date = Apr 1998 | title = Secretion of growth hormone in patients with chronic fatigue syndrome | url =https://linkinghub.elsevier.com/retrieve/pii/S1096637498800361 | journal = Growth Hormone & IGF Research|language=en | volume = 8 | pages = 127β129|doi=10.1016/S1096-6374(98)80036-1}}</ref><ref>{{Cite journal | last = Moorkens | first = G. | last2 = Wynants | first2 = H. | last3 = Abs | first3 = R. | date = Apr 1998 | title = Effect of growth hormone treatment in patients with chronic fatigue syndrome: A preliminary study | url = https://linkinghub.elsevier.com/retrieve/pii/S1096637498800373 | journal = Growth Hormone & IGF Research|language=en | volume = 8 | pages = 131β133|doi=10.1016/S1096-6374(98)80037-3}}</ref><ref>{{Cite journal | last = Johansson | first = Madeleine | last2 = Ricci | first2 = Fabrizio | last3 = Schulte | first3 = Janin | last4 = Persson | first4 = Margaretha | last5 = Melander | first5 = Olle | last6 = Sutton | first6 = Richard | last7 = Hamrefors | first7 = Viktor | last8 = Fedorowski | first8 = Artur | date = 2021-04-21 | title = Circulating levels of growth hormone in postural orthostatic tachycardia syndrome | url =https://www.nature.com/articles/s41598-021-87983-5 | journal = Scientific Reports|language=en | volume = 11 | issue = 1 | pages = 8575|doi=10.1038/s41598-021-87983-5|issn=2045-2322}}</ref> Anecdotally, some ME/CFS patients have tried pyridostigmine (trade name [[Mestinon]]), with some success.<ref>{{Cite news |url =http://www.healthrising.org/blog/2016/06/17/mestinon-chronic-fatigue-vagus-nerve-stimulation-exercise/ | title = A Mestinon Miracle: Vagus Nerve Stimulating Drug Helps Long Time ME/CFS Patient Exercise - Health Rising | date = 2016-06-17|work=Health Rising | access-date = 2018-08-10|language=en-US}}</ref> A work in progress study of [[exercise intolerance]] in [[preload failure]] found that Mestinon improved exercise tolerance, but the study has not yet been published.<ref>{{Cite journal | last = Oliveira | first = R.K. | date = 2016 | title = Pyridostigmine for Exercise Intolerance Treatment in Preload Failure | url =https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts.A5664 | journal = American Journal of Respiratory and Critical Care Medicine | volume = | pages=|via=}}</ref>
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