The following is only meant for people with neurological ME as defined by the Charitè CFS/ME center in 10.1016/j.bbi.2015.09.013. They define the disease's mechanism to be mediated by adrenergic- and muscarinergic-binding subtypes of acetylcholine-receptor antibodies. Acetylcholine-receptor antibodies are commonly found in various neuromuscular diseases. The referenced paper discusses the specific subtypes and for which condition they are usually found. Unlike ME, these conditions have a longer research history and approved medical treatment options (e.g. Myasthenia Gravis (MG) 10.1016/j.ncl.2018.01.011). A common and early neuromuscular medication with immediate effect on the acetylcholine receptors are cholinesterase inhibitors. Their goal is to enhance the acetylcholine concentration at the receptor site and thereby enhance transmission (PMID:31335056). Pyridostigmine is one of them, and I've read other users mentioning this already. They can normalize the function of the receptors if administered the right dosage. Overdosage can have critical complications, though. This is why synthetic cholinesterase inhibitors aren't available without a prescription and should not be taken without medical advice. They are not approved for ME. The typical synthetic cholinesterase inhibitor targets muscle function. This not only affects skeletal muscles but smooth muscles as well. Smooth muscles can be found in the iris, the esophagus, the remaining gastrointestinal system, the airway, and other places where muscle tonus is maintained without cognitive stimulus. To give some context, asthma patients have high tonus in the airway smooth muscle (10.1152/japplphysiol.00950.2012). If their cholinesterase activity was inhibited, the muscle tonus would be further enhanced, amplifying the asthmatic effects. Different cholinesterase inhibitors have different effects on skeletal vs. smooth muscle tonus (10.1097/00000539-200101000-00020). Muscle nerve endings are not the only cell type expressing acetylcholine receptors, though. All subunits associated with ME, as identified by Charitè CFS/ME center, (i.e. β2, M3, M4) serve different purposes in the brain (10.1016/j.neuron.2012.08.036). Under normal conditions, typical synthetic cholinesterase inhibitors such as Pyridostigmine don't cross the blood-brain barrier (10.1038/nm1296-1382). Their purpose is to treat neuromuscular diseases, and brain toxicity can be avoided this way regardless of dosage. Since ME dominantly affects the brain, my question is, what alternatives exist that target the brain and avoid effects on the muscle tonus. Rationally, a substance with high blood-brain permeability will lower the dosage requirements and hence reduce potential muscle-related complications. Alzheimer's is a disease for which this assumption has been integrated into therapeutic choices (10.3892/mmr.2019.10374). The referenced paper lists different cholinesterase inhibitors and their effects in the context of Alzheimer's. Fortunately, non-synthetic options exist here. While research on flavonoids lack differentiation and depth, and Cardanol extraction from the cashew nutshell isn't unproblematic from health and ethical standpoints, Huperzine sounds like a promising nutritional choice to me. Huperzine A is an extract from club moss plants (WebMD). Naturally, research on herbally-extracted agents is limited. Yet, the available research shows Huperzine A to have "better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action" (10.1111/j.1745-7254.2006.00255.x). Exceeding the recommended dosage limit of 200μg b.i.d., mild side effects could be experienced with 400μg b.i.d (10.1038/aps.2012.128). As for most herbal extracts, toxicity is still an option if severely overdosed (10.32725/jab.2009.009). Huperzine A is available over the counter and isn't restricted to Alzheimer's disease therapy. Some healthy people use it just as a neuro booster. Still, be considerate before trying new things.