After discovering the majority of patients with CFS/ME appeared to suffer with anticholinergic syndrome, attempts to formulate a compound to boost acetylcholine in the central, peripheral, and autonomic nervous systems began. Objective measures of success included the ability of the compound to trigger the postganglionic vagus nerve, resulting in a bowel movement. Out of 27 patients studied, 88% reported a bowel movement within 90 minutes of ingesting the patented compound (Parasym Plus™). A dramatic increase in mental/physical energy was reported by 93%. Parasym Plus™ can be effective in reversing many symptoms of CFS/ME.
Genetic Disease Investigators conducted an analysis of signs and symptoms reported by 177 patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Results revealed that the majority of patients suffered with symptoms and signs of anticholinergic syndrome (low acetylcholine levels). Symptoms involved abnormalities in the autonomic nervous system, the central nervous system and the peripheral nervous system. Research then turned to why acetylcholine levels were low, and importantly, to explore the possibility of providing patients immediate relief by increasing levels of acetylcholine. If successful, many symptoms of autonomic dysfunction (orthostatic intolerance, tachycardia, gastroparesis, poor digestion, poor gallbladder function and others), central nervous system dysfunction (brain fog, cognitive decline, mood swings, irritability and others) and peripheral nervous system symptoms (extreme fatigue, tremor, loss of coordination and others) could potentially be alleviated.
Because acetylcholine is required for multiple nervous systems of the body, a replacement compound needs to be available in the brain (central nervous system), the muscles (peripheral nervous system) and the organs (autonomic nervous system). Because acetylcholine itself is not a drug (it is broken down immediately by the body), a replacement compound needed to be created that was easily and safely absorbed by the body. Additional goals for this compound were as follows:
- The ingredients needed to assimilate in the body rapidly in order to stimulate the (postganglionic) vagus nerve to assist with all aspects of digestion (autonomic nervous system). Such vagus nerve stimulation could also improve immune system function and decrease systemic inflammation.
- The levels of acetylcholine needed to increase in the central nervous system (brain) to help alleviate symptoms of “brain fog,” cognitive decline and poor short-term memory. To accomplish this, all ingredients are needed to cross the blood-brain barrier.
- The ingredients could not activate histamine-producing cells (or any aspect of inflammation).
- The ingredients needed to be within what the FDA has already determined to be safe.
- The combination of ingredients needed to be effective regardless of genetic defects involving the production of acetylcholine, should such defects be present.
The vagus nerve in CFS/ME
The vagus nerve (part of the autonomic nervous system) controls most aspects of digestion, inflammation, and immune function, and because abnormalities in all of these conditions are considered significant contributors of symptoms in CFS/ME, focus on vagus nerve response was a critical aspect of research. The ability of the compound to trigger the (postganglionic) portion of the vagus nerve was an essential goal.
The vagus nerve controls most aspects of proper digestion including peristalsis of the food down the esophagus and through the intestines, opening of the pyloric valve at the base of the stomach (allowing food to pass into the intestines), the proper production of stomach acid required for digestion (and the absorption of numerous vitamins), the release of bile by the gall bladder, the release of digestive enzymes by the pancreas, and the opening of the Sphincter of Oddi (allowing the release of bile and pancreatic enzymes into the intestines). Many patients with CFS/ME suffer with delayed gastric emptying/gastroparesis/constipation, and other manifestations of gut dysfunction and irritable bowel syndrome (IBS).  Gut inflammation has been proposed to be a significant contributor of symptoms in this population. 
Immune system function has also been found to be adversely affected in CFS/ME.  Studies have found evidence of dramatic disturbances of immunity, including alteration in cytokine profiles in CFS/ME patients.  Numerous aspects of cellular immunity have been found to be abnormal and are considered to be a key component of the disease.  Proper functioning of the vagus nerve is critical for normal immune system function because the vagus nerve controls the function of the spleen, a key organ in both innate and adaptive immunity. 
As the cholinergic anti-inflammatory pathway of the body, proper triggering of the vagus nerve can also decrease systemic inflammation.   The vagus nerve helps control inflammation both through its innervation of the spleen and through its control of inflammatory cells.  These inflammatory cells contain alpha-7 subunit-containing nicotinic acetylcholine receptors which, when properly stimulated by the vagus nerve, control the release of inflammatory cytokines. This control links the inflammatory reflex to immunity, and proper functioning is critical to control abnormal inflammation often found in CFS/ME. Disorders of the inflammatory pathway can exhibit as neuroinflammation, cardiovascular disorders and gut inflammation in CFS/ME and appear to be a critical component to symptoms of illness.  
Results of Treatment Trials
When eliciting a response to treatment, objective measures are preferable to subjective responses. The objective finding of a bowel movement within 90 minutes of ingesting the compound (repeatable over two consecutive days) was considered an objective, positive response (indicating vagus nerve stimulation). Subjective responses (improvement in cognition, mental and physical energy) were also collected.
Twenty-seven (27) patients with CFS/ME volunteered to participate in treatment trials of the compound (now known as “Parasym Plus™”). All patients were over the age of 12 and were not taking Adderall, opioids, cholinergic or anticholinergic medications (medications that could mask the vagus nerve response). Patients were instructed to take the compound on an empty stomach, preferably in the morning prior to eating.
|# of patients tested||27||Percent|
|Age y||32 +/- 13|
|Positive for bowel movements within 90 minutes||24||88%|
|Increase in mental/physical energy||25||93%|
Response of patient testing was dramatic. Twenty-four (24) out of 27 patients reported a bowel movement within 90 minutes of taking the ingredient mix, despite long-standing constipation/gastroparesis. This response was repeatable (occurring two consecutive days, at a minimum). Additionally, 25 out of 27 patients reported a significant improvement in both physical and mental energy.
Although preliminary, such a dramatic response suggests that the majority of patients with CFS/ME may indeed be suffering with low levels of acetylcholine, contributing to illness. Perhaps more importantly, this demonstrates that effectively replacing the acetylcholine appears to alleviate many symptoms of illness.
These findings also suggest alternative explanations for many cases of POTS – Postural Orthostatic Tachycardia Syndrome, a commonly overlapping condition with CFS/ME. Currently, research has considered abnormal receptors of the autonomic nervous system (acetylcholine receptors) as a cause of autonomic dysfunction in POTS and CFS/ME. As stated by Loebel et al. “autonomic dysregulation in CFS/ME points to an autoimmune disease directed against the neurotransmitter receptors”. Such abnormalities can be found in autoimmune autonomic ganglionopathy and research has delved deeply into the search for obscure autoimmune conditions that may be affecting these patients.   
Instead, this new research indicates that rather than a disorder affecting (acetylcholine) receptors, the majority of these patients may be suffering with a neurotransmitter problem (low acetylcholine levels).
The research of Genetic Disease Investigators, LLC continues to investigate the cause of acetylcholine decline and to determine if the (initial) decrease of acetylcholine could be the cause of changes to the receptors found in some patients. Meanwhile, boosting acetylcholine levels while simultaneously stimulating the postganglionic portion of the vagus nerve (with patented Parasym Plus™) is effectively reversing numerous symptoms of CFS/ME.
 Burnet R, Chatterton B. Gastric emptying is slow in chronic fatigue syndrome. BMC Gastroenterol. 2004;4:32.
 Gamborone JE, Gorard DA, Dewsnap PA, eta l. Prevalence of irritable bowel syndrome in chronic fatigue. J R Coll Physicians Lond. 1996 Nov-Dec;30(6):512-3.
 Lakhan S, Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010;7:79.
 Thayer J, Sternberg E. Neural aspects of immunomodulation: Focus on the vagus nerve. Brain Behav Immun. 2010 Nov;24(8):1223-1228.
 Pavlov VA, Tracey KT. Neural circuitry and immunity. Immunul Res. 2015 Dec;63(1-3):38-57.
 Lorusso L, Mikhaylova SU, Capelli E. Immunological aspects of chronic fatigue syndrome, Autoimmun Rev. 2009 Feb;8(4):287-91.
 Natelson B, Haghighi M, Ponzio N. Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Clin Diagn Lab Immunol. 2002 Jul;9(4):747-752.
 Barker E, Fujimura SF, Fadern MB, et al. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S136-41.
 Pollack S. Chronic fatigue syndrome and immune dysfunction: cause or effect? Isr Med Assoc J. 2002 Nov;4(11 Suppl1):883-5.
 Trion Am, Vasilescu C. Role of the spleen in immunity. Immunologic consequences of splenectomy. Chirurqia (Bucur). 2008 May and Jun;103(3):255-63.
 Wluka A, Olszewski WC. Innate and adaptive processes in the spleen. Ann Transplant. 2006;11(4):22-9.
 Ulloa L. the vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov. 2005 Aug;4(8):673-84.
 Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. Auton Neuroscr. 2014 May;182:65-9.
 Pavlov V, Tracey K. the vagus nerve and the inflammatory reflex – linking immunity and metabolism. Nat Rev Endocrinol. 2012 Dec;8(12):743-754.
 Matteoli G, Gomez-Pinilla PJ, Nemethova A, et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut. 2014 Jun;63(6):938-48.
 Nakatomi Y, Mizuno K, Ishii A, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: An C-(R)-PK11195 PET study. J Nucl Med. 2014 Jun;55(6):945-50.
 Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders of the inflammatory and oxidative and nitrosative stress (IO & NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett.2009;30(6):677-93.
 Loebel M, Grabowski P, Heidecke H, et al. Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. Sep 21 2015. doi:10.1016/j.bbi.2015.09.013
 Li J, Zhang Q, Liao Y, et al. The value of acetylcholine receptor antibody in children with postural tachycardia syndrome. Pediatr Cardiol. 2015;36:165-170.
 Raj S, Black B, Biaggioni I, et al. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. American Heart Association Scientific Sessions 2004, New Orleans, LA Nov 7-10, 2004. Abstract in Circulation. 2004;110[supl III]111-460.
 Thieben M, Sandroni P, Sletten D, et al. Postural Orthostatic Tachycardia Syndrome: The Mayo Clinical Experience. Mayo Clin Proc. 2007;82(3):308-313.
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