Is Neurochemistry Overlooked in ME/CFS and Long COVID Research?

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Despite decades of effort, ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and Long COVID remain poorly understood. One possible reason may be the continued underrepresentation of neurochemical research in these fields. In biomedical science, certainty comes only when cause and effect are demonstrated through rigorous laboratory and imaging tools—yet much of the research on these conditions still skirts around the complex interplay of brain function, hormonal regulation, and psychological symptoms.

The Neurobiology of Depression: A Parallel Worth Revisiting

There’s a familiar pattern in research on chronic, poorly-defined illnesses: a search for answers that tends to overlook what's been apparent for years—the central role of the brain in both physiological and psychological dysfunction.

Beyond well-documented cases of direct brain infections from pathogens, the underlying mechanisms of hormonal and neurochemical imbalance—particularly involving the hypothalamic-pituitary-adrenal (HPA) axis—remain insufficiently explored.

This gap became clearer to me after a recent conversation with someone dismissive of these issues, which reminded me of a lecture by Prof. Robert Sapolsky that I had watched about a year ago. Revisiting it, I noticed striking connections that seemed relevant to both ME/CFS and Long COVID.

Around the 24-minute mark, Sapolsky makes a notable point:

“Atypical depression seems to have a lot of biochemistry in common with chronic fatigue syndrome.” (24:09)
Just seconds later, he adds:
“…a variance of long-haul COVID, the type that is still flattening you years later.” (24:18)

These observations reignited a question I’ve long had: Are ME/CFS and Long COVID research efforts neglecting core neurochemical pathways?

Key Patterns Observed

Two neuroendocrine patterns stand out, both frequently present in ME/CFS and Long COVID patients:

  1. Low Cortisol States
    Often associated with fatigue, anxiety, and depression—but interestingly, individuals in this state may exhibit heightened perceptiveness and a more accurate grasp of reality.

  2. High Cortisol + Elevated Dopamine
    A profile often found in individuals with high-functioning stress responses, sometimes leading to shallow, dismissive attitudes and cognitive rigidity—especially when sustained artificially (e.g., via stimulants or constant stress reinforcement).

These patterns mirror not only atypical depression but may also relate to the persistent cognitive issues described as “brain fog”—possibly better framed as neuroinflammation.

The Case for Neurochemical Testing

Despite these well-documented overlaps, ME/CFS and Long COVID research have yet to incorporate consistent neurochemical screening protocols. A rational starting point could include:

  • Catecholamine Testing (Blood/Urine):
    Measuring dopamine, norepinephrine, and epinephrine levels as a basic screen for neurochemical imbalance. While not brain-specific, these values can offer a broader view of systemic hormonal dysregulation.

  • DaTscan (Dopamine Transporter Imaging):
    A more precise tool, the DaTscan is a SPECT imaging technique that assesses dopamine transporter density in the brain. This could provide objective insight into central dopaminergic activity and potential dysfunction in ME/CFS and Long COVID patients.

Final Thoughts

The overlap between atypical depression, ME/CFS, and Long COVID—particularly in terms of neuroendocrine function and neurotransmitter dynamics—warrants deeper investigation. 

These conditions may share not just symptom profiles but underlying biochemical mechanisms. 

Until neurochemistry becomes a standard part of research in these fields, crucial pieces of the puzzle may remain missing.

References:  

Fixing Brain Fog: Part 1: https://www.greatlakesneurology.com/post/fixing-brain-fog-part-1#:~:text=When%20cortisol%20levels%20are%20imbalanced%2C%20people%20can,ability%20of%20serotonin%20receptors%20in%20the%20brain.

A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008956#:~:text=Cortisol%20(CORT)%20in%20humans%2C,affected%20brain%20regions%20%5B19%5D.

© 2025-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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