What Amino Acids Are Involved in Chronic Fatigue Syndrome?

November 15, 2025 •

3 min read

Chronic fatigue syndrome (ME/CFS) is a complex, debilitating multisystem disorder characterized by long-term fatigue not explained by other medical conditions. Emerging research reveals specific amino acid dysregulation that can disrupt crucial energy production pathways, potentially explaining some core symptoms.

Quick Summary

Studies show metabolic dysfunction in ME/CFS involves disrupted amino acid pathways, affecting energy production and contributing to core symptoms. Changes are observed in branched-chain amino acids, glutathione precursors, and tryptophan, influencing mitochondrial function, oxidative stress, and neurotransmitter balance.

Key Points

Altered Energy Metabolism: Specific amino acids involved in generating energy, like the BCAAs leucine, isoleucine, and valine, often show reduced levels in ME/CFS patients.
Oxidative Stress & Glutathione: Deficiencies in the amino acid precursors for glutathione (glutamate, cysteine, glycine) lead to lower antioxidant levels and increased oxidative stress, which damages mitochondria.
Disrupted Serotonin Pathway: Alterations in tryptophan metabolism, particularly through the kynurenine pathway, affect serotonin levels and are linked to both inflammation and neurological symptoms.
Serine and Glycine Imbalance: Studies show increased serine and disrupted one-carbon metabolism, suggesting impaired cellular methylation and nucleotide synthesis crucial for cellular repair and function.
Mitochondrial Dysfunction: The collective impact of these amino acid and metabolic imbalances points to impaired mitochondrial function, which directly contributes to the severe fatigue experienced in ME/CFS.
Gender Differences: Notably, some amino acid changes, such as reduced levels related to oxidative metabolism, are more pronounced in female ME/CFS patients.
Treatment Implications: Research into these amino acid pathways opens doors for targeted nutritional and supplement-based strategies, though conclusive evidence is still developing.

Research into the metabolic dysfunction underlying chronic fatigue syndrome (ME/CFS) has identified several amino acids and related pathways that are frequently disturbed in patients. These disruptions often point to issues with energy production, oxidative stress, and neurotransmitter function, which are central to the illness's debilitating symptoms. The specific amino acids involved and the nature of their alterations are complex and can differ between patients.

The Role of Branched-Chain Amino Acids (BCAAs)

Branched-chain amino acids (leucine, isoleucine, and valine) are important for muscle energy. Some studies, particularly in women with ME/CFS, indicate lower serum BCAA levels, suggesting altered energy metabolism where the body might use different fuels for the TCA cycle. Studies have noted reduced levels of BCAAs and their intermediates during exhaustion in ME/CFS. This pattern differs from inactivity-related changes, suggesting a disease-specific metabolic shift.

Disturbances in Tryptophan and Serotonin Pathways

Tryptophan is an essential amino acid and a precursor to serotonin. Research points to complex tryptophan metabolism issues in ME/CFS. Lower tryptophan levels are reported in some patients, possibly due to increased metabolic demand. Dysregulation of the kynurenine pathway, a main route for tryptophan breakdown influenced by inflammation, is also proposed.

Glutathione Synthesis and Oxidative Stress

Oxidative stress, an imbalance of free radicals and antioxidants, is a key feature of ME/CFS. Glutathione, a major antioxidant, is made from glutamate, cysteine, and glycine. Studies show significantly lower glutathione levels in ME/CFS patients, possibly due to limited precursors like cysteine or increased oxidative stress. Reduced glutathione impairs the ability to combat oxidative damage, contributing to mitochondrial dysfunction, fatigue, and pain.

The Serine-Folate-Glycine Pathway

Metabolomic research highlights imbalances in the serine-folate-glycine pathway, important for methylation and energy. Some studies find elevated serine and decreased related metabolites like 5MTHF in ME/CFS patients. This dysregulation can affect crucial cellular processes. One study noted differing post-exercise metabolic responses in this pathway between ME/CFS patients and healthy individuals.

Comparison of Amino Acid Involvement in ME/CFS


Amino Acid Group	Role in Healthy Metabolism	Observed Change in ME/CFS	Impact on Symptoms
Branched-Chain (BCAAs)	Fuel for oxidative metabolism, muscle protein synthesis, and central fatigue moderation	Lowered serum levels, especially in female patients and after exertion	Impaired energy production, potential for muscle pain and post-exertional malaise
Tryptophan	Serotonin precursor, immune regulation via kynurenine pathway	Decreased availability or altered metabolic breakdown	Mood disturbances, pain, sleep issues, and possibly an enhanced inflammatory response
Glutathione Precursors (Cysteine, Glycine, Glutamate)	Synthesis of the antioxidant glutathione, protecting cells from oxidative stress	Depleted glutathione levels, suggesting increased oxidative stress and/or impaired synthesis	Increased oxidative damage, mitochondrial dysfunction, leading to fatigue and pain
Serine & Glycine	One-carbon metabolism, methylation, and nucleotide synthesis	Elevated serine, disrupted folate and methylation pathways	Dysregulated energy production, potential myelin dysfunction, and impaired nerve health

Addressing Metabolic Disturbances

Amino acid imbalances suggest potential nutritional interventions, though robust clinical trial evidence is limited. Supplementation may support impaired pathways, but results vary. Strategies to boost glutathione (e.g., NAC) target oxidative stress. Other supplements like CoQ10 and L-carnitine are sometimes used for mitochondrial support, with mixed evidence. The complex nature of ME/CFS requires a holistic approach, as no single intervention is likely a cure.

Conclusion

The involvement of specific amino acids in chronic fatigue syndrome indicates significant underlying metabolic issues. Changes in BCAAs, tryptophan, glutathione synthesis, and the serine-folate-glycine pathway contribute to core ME/CFS features like energy deficits and oxidative stress. While more research is needed, these findings offer critical insights and potential therapeutic targets beyond symptom management, guiding future research and clinical strategies.

What amino acids are involved in chronic fatigue syndrome?

Frequently Asked Questions

The primary issue is metabolic dysfunction that impairs energy production. Studies have found altered levels of amino acids, particularly reduced concentrations of those that fuel oxidative metabolism, which leads to inadequate ATP generation.

No, studies indicate that specific amino acid pathways are more affected than others. For example, branched-chain amino acids (BCAAs), tryptophan, and precursors for glutathione are frequently cited, while other amino acids may show less consistent changes.

Tryptophan is a precursor to serotonin. Its dysregulation is linked to altered serotonin activity and changes in the inflammatory kynurenine pathway, which can contribute to mood disturbances, pain, and sleep issues commonly experienced in ME/CFS.

Glutathione is a key antioxidant. Patients with ME/CFS often have depleted glutathione levels due to oxidative stress, which impairs mitochondrial function and increases cellular damage, thus contributing to severe fatigue and pain.

While some nutritional interventions, including supplements like CoQ10, L-carnitine, and certain antioxidants, are anecdotally reported or suggested in research, there is not yet conclusive evidence for universal effectiveness. Any dietary changes or supplementation should be done under medical supervision.

Some research, such as findings by Fluge et al., noted differences in how men and women metabolically adapt. Female patients showed reductions in certain oxidative-fueling amino acids, whereas male patients had an increase in a marker of protein catabolism.

Studies suggest it is not. Researchers have noted that the specific amino acid changes observed in ME/CFS patients do not match the patterns of inactivity-related metabolic changes seen in healthy, deconditioned individuals. This suggests a unique, disease-specific metabolic alteration.