Also, the cholinergic hypothesis of CFS was popular back around 2003-2004, but a randomized controlled trial of the reversible cholinesterase inhibitor galantamine failed, and then researchers lost interest in this hypothesis. As usual, there are so few resources in CFS research that researchers are quick to abandon a paradigm before it is thoroughly investigated- it might be the case that some other approach would have worked. We of course had the same situation with herpesviruses. Researchers lost interest after valtrex failed a placebo controlled trial and it took 10 years before doctors began to study more powerful drugs such as valcyte. The problem with treating autonomic dysfunction with drugs is that this is trying to replace a dynamic system with a relatively static system. In a healthy person, the parasympathetic and sympathetic nervous systems are in a balance that can change within seconds when the body is exposed to stress from standing up, exercise, eating, etc. In CFS, we see several things indicating that this *flexibility* in the system is lost. When lying down or resting, CFS patients have higher resting heart rate and supine blood pressure than healthy people- so they don't get the relaxation response. This indicates parasympathetic/cholinergic deficit. When standing, some patients show more of this with a POTS type pattern of rapid heart rate, while others show low blood pressure (lack of sympathetic tone). When exercising, a subgroup of patients fails to increase their heart rate/blood pressure in response to exercise (sympathetic deficit). So, patients' systems are inflexible. You can see why this would be hard to treat with drugs that activate one system or another. This doesn't really make up for the lack of ability to change the system in response to physical stress. But, if it is caused by autoantibodies, approaches to remove the autoantibodies may work.