The science

The big picture

Research is converging on a loop:

1. The autonomic nervous system (the automatic system that controls heart rate, blood pressure and blood flow) doesn't work properly.
2. Less blood reaches the brain and muscles, especially when upright or active.
3. Cells run short of oxygen and switch to an inefficient backup energy system. Their energy factories (mitochondria) get damaged.
4. Post-exertional malaise follows as the body struggles to clean up and repair.

Autoantibodies, immune dysfunction and brain inflammation may drive this loop in some patients. Different people may be affected at different points, which could explain why no single treatment works for everyone.

The brain and neuroinflammation

• Imaging meta-analysis (2023): 65 brain imaging studies covering 1,529 patients concluded that neuroinflammation (inflammation in the brain) is the most convincing explanation. It found abnormalities in hub areas that connect reasoning and emotion. Observational
• An earlier review of 55 studies found widespread disruption of the brain network that controls the autonomic nervous system. Observational
• Important nuance: this isn’t the severe brain inflammation seen in encephalitis. The evidence points to low-level inflammation, possibly from an immune response to the original infection that never fully switched off.
• White matter study (March 2026, Human Brain Mapping): 67 patients and 67 healthy people were compared using a new imaging measure of neuroinflammation. This could become a biomarker (an objective test). Observational
• The “sickness response” model (Komaroff review, September 2026): infection and inflammation activate circuits in the hypothalamus and brainstem that produce fatigue, pain, brain fog and sleepiness. This is a normal protective programme that, in ME/CFS, fails to switch off. Hypothesis
• Johns Hopkins (ongoing): testing whether a leaky blood-brain barrier lets immune cells into the brain and drives cognitive problems.

The brain’s waste-clearance system

Every night during sleep, the brain flushes out metabolic waste through what’s called the glymphatic system.

• Griffith University (July 2026) showed for the first time that this system is impaired in ME/CFS, and that worse function was linked to worse sleep and more brain fog. Observational
• Why it matters: it suggests a direct link between poor sleep and brain fog. Broken sleep means less clean-up time, which means more fog. It’s one reason to check for sleep disorders like sleep apnoea.

Blood flow to the brain

• Reduced blood flow to the brain is common. A 2025 review found it in 12 ME/CFS studies. It was worse in people who also have orthostatic intolerance. One study found blood flow to the brain’s emotional centre was about 34% lower than in healthy people. Observational
• The brainstem: evidence points to problems in brainstem support cells and in the connections between the brainstem and the hypothalamus, which control blood vessels.
• Brigham & Women’s Hospital (January 2026): found that in both Long COVID and ME/CFS, blood flow to the brain drops when upright, even without a rise in heart rate or a drop in blood pressure. The cause was breathing out too much carbon dioxide (“hypocapnic cerebral hypoperfusion”). Observational

• Speculative: a 2026 paper proposed that some severe cases may involve instability where the skull meets the neck. This is a hypothesis only. Hypothesis

Muscles and energy: the “two engines”

Stanford whole-body PET scan (presented May 2026): researchers expected to see brain inflammation. Instead they found strong signals in the muscles (thighs, shoulders) that matched how fatigued people were. It supports a model where poor blood flow causes a self-reinforcing cycle of damage in muscle energy factories. Observational

Here’s the plain-language version of what seems to be going on.

In ME/CFS, the switch to the backup engine trips far too early, for a shower or a conversation rather than a sprint. When that happens:

• energy runs short, which causes weak legs and slow thinking
• lactate and acid build up, bringing heavy limbs and malaise
• the mitochondria take damage and get even worse at their job

PEM is that cascade playing out over 24–48 hours as the body tries to clean up and repair. It’s also why pacing works: staying below the switch point avoids the damage.

The immune system and TRPM3 (Griffith University)

Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) in Queensland has argued for a decade that ME/CFS is an ion channel disorder.

• A calcium channel called TRPM3 on natural killer (NK) immune cells doesn’t open properly, so calcium can’t get in and the cell can’t do its job.
• TRPM3 is also found in the brain, brainstem, muscles and heart. That could explain how one faulty channel causes symptoms all over the body.
• The drug naltrexone removes a brake on TRPM3. In the lab, it restored the channel’s function. Lab study

Strengths: five groups of patients, two techniques, two illnesses, all with consistent results. That is unusual in ME/CFS research. Limitations: very small samples (9–10 per group), lab doses far higher than what a tablet achieves, and no controlled clinical results yet. The researchers also hold a patent on a TRPM3-based test.

Griffith is now starting a placebo-controlled trial of LDN in ME/CFS and Long COVID (TreatMELC). See trials and the LDN section.

Genetics: DecodeME

The world’s largest ME/CFS genetics study compared more than 15,000 people with ME/CFS against about 260,000 controls. It found eight genetic signals, mainly in the immune and nervous systems. ME/CFS is polygenic (many genes, each with small effects), and there’s no link to the classic autoimmune genes. Observational More on DecodeME.

Blood tests in development

There’s no approved diagnostic test yet, but several are being developed:

• Edinburgh (2025, EMBO Molecular Medicine): blood markers for ME/CFS that were replicated in a second group and weren’t explained by inactivity. Observational
• Cornell: a model based on RNA fragments in the blood was about 77% accurate. Not yet a clinical test.
• EpiSwitch (a commercial test) claims 96% accuracy in a small group. Treat this sceptically until other researchers replicate it.

The biggest lesson of 2026

Trials that tested a drug on all patients failed, but in several of them some patients clearly responded, and those responses were buried in the overall “no effect” result. This happened with LDN, immunoadsorption and BC007. Researchers are now selecting patients by biomarker so each treatment is tested on the people it’s most likely to help. See 2026 results.