Acetyl-CoA and SAMe for the Parasympathetic Nervous System

A short introduction:

I was first diagnosed with gut dysbiosis and Adrenal Fatigue and treated accordingly. I had irregular cortisol in the tests. So I did not come in contact with ME/CFS directly at first. When I searched on the internet I rather looked at treatments for adrenal fatigue and direct symptoms, than to find out what symptoms ME/CFS is related to.

I suffered from some sensitivity to touch and sound and sometimes light (eyes). But I related these symptoms to the adrenal fatigue and to me being sensitive as a person (‘highly sensitive person’), but I didn’t know many people in ME/CFS experienced these symptoms too.

When I found out, it confused me. Probably because I hadn’t related to hypersensitivity to fatigue or low energy levels in general.

Low energy levels can have multiple aspects in disease, like low energy levels in the heart may lead to certain heart diseases.

In ME/CFS low energy levels seem to  cause fatigue, but further impact the transfer of stimuli in the nervous system. The body’s ability to filter and deal with physical and emotional stimuli seems to be reduced.
There are neurotransmitters that have the effect of increasing stress and input, like glutamate or epinephrine, while other ‘calming’ neurotransmitters like GABA, serotonin or acetylcholine rather have the effect of reducing input. They activate the parasympathetic nervous system, which brings the body into a state of relaxation.

Parasympathetic Nervous System and Energy Metabolism

The parasympathetic nervous system has some antagonistic functions to the sympathetic nervous system. While the function of the sympathetic nervous system increases in a state of stress and as a danger response, the parasympathetic nervous system is described as the ‘rest-and-digest’-mode. The parasympathetic nervous system influences functions, like slowing heart rate and increasing digestion. Many ME/CFS patients have symptoms that are associated with a dysregulation in the parasympathetic and sympathetic nervous system, like decreased digestive function or increased heart rate (1).

I think the activation of the parasympathetic nervous system depends on sufficient energy levels in the body, even in healthy people. If you are hungry, you cannot relax. ME/CFS patients might have problems producing enough energy and this energy depletion can reduce the activation of the parasympathetic nervous system. Some calming neurotransmitters seem to be affected negatively by low energy levels.

Two metabolites could be especially relevant to activate the parasympathetic nervous system:
Acetyl-CoA and S-Adenosyl methionine (SAMe).


Glucose is broken down to pyruvate and then converted to acetyl-CoA . The fatty acid oxidation  and the breakdown of different amino acids also produce acetyl-CoA.

A dysfunctional pyruvate dehydrogenase and low acetyl-CoA-production might lead to increased breakdown of the amino acid tryptophan for energy production. Tryptophan is the precursor of the neurotransmitter serotonin. acetyl-CoA is also required for the synthesis of the neurotransmitter acetylcholine. Serotonin and acetylcholine both activate the parasympathetic nervous system.

A study from 2016 found indications for impaired pyruvate dehydrogenase function in ME/CFS patients (2), which might also conclude that depleted acetyl-CoA plays a role in ME/CFS, lowering acetylcholine and serotonin levels.


S-Adenosyl methionine (SAMe)

S-Adenosyl methionine is produced in the methionine cycle and has the ability to transfer methyl groups onto other substances.

In the neurotransmitter metabolism SAMe is required for the breakdown of stress-neurotransmitters like dopamine, noradrenaline and adrenaline. Also the synthesis of phosphatidylcholine requires three methyl groups. phosphatidylcholine can  produce choline, choline and acetyl-CoA react to acetylcholine. SAMe is  important to break down stress-transmitters and synthesize acetylcholine to activate the parasympathetic nervous system.



Functioning SAMe- and acetyl-CoA-production might be important in CFS/ME for the levels of serotonin and acetylcholine and to break down stress neurotransmitters, so that the parasympathetic nervous system can be activated.

This might imply that supplements that tend to increase the requirement for acetyl-CoA or SAMe could be counterproductive.


  2. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome