Chronic Fatigue Syndrome (ME/CFS) and Nitric Oxide

Short answer: chronic fatigue syndrome (ME/CFS) is an energy problem at the level of the cell. The mitochondria are under pressure, the gate that lets fuel into them is jammed, and the blood vessels that should deliver oxygen make less healthy nitric oxide. In about half of people with ME/CFS, the artery lining measurably underperforms. My approach is simple to say and slow to do: pace, lower the load, open the exits, then rebuild the engine and restore blood flow. Detoxification, nitric oxide and medicinal mushrooms are the three tools I lean on most.

Key takeaways

• ME/CFS is measurable. Metabolic studies show a jammed fuel gate (PDH), a "cell danger" lockdown and a drop in performance on a second exercise test 24 hours later.
• In one study, 51% of people with ME/CFS had peripheral endothelial dysfunction against 20% of healthy controls, and those with it were more unwell.
• Blood plasma from people with ME/CFS lowered nitric oxide production in endothelial cells in the lab, pointing to "something in the blood" suppressing the NO enzyme.
• Viruses, mould, chemicals, surgery and major stress commonly come before onset. The infection is often the last straw, not the first.
• Reishi outperformed placebo for fatigue-type symptoms in a 132-person trial. Cordyceps supports oxygen use and energy.

What is chronic fatigue syndrome?

ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) is profound fatigue that rest doesn't fix, with a signature feature: post-exertional malaise. Effort, physical or mental, triggers a crash 12 to 72 hours later. It usually comes with unrefreshing sleep, brain fog, dizziness or a racing heart on standing, and sensitivity to chemicals, noise and light.

It is not laziness, deconditioning or depression. Deconditioned people improve with exercise; people with ME/CFS crash after it. That difference is measurable. On two exercise tests 24 hours apart, healthy people repeat their result. People with ME/CFS drop on day two.

What's happening inside the cell

Every heartbeat, thought and step runs on ATP. Making it needs four things: fuel delivered by the blood, a gate that lets fuel into the mitochondria, an engine with all its parts, and an exhaust system that keeps up. In ME/CFS all four are under pressure at once.

• The gate is jammed: the enzyme pyruvate dehydrogenase (PDH) underperforms, so cells burn fuel inefficiently and make lactate with little effort. That is the heavy, poisoned feeling in the muscles.
• The cell is in lockdown: blood metabolites resemble a "cell danger response", where after a virus or toxin, cells turn energy production down to protect themselves and stay down.
• Less blood to the brain upright: tilt studies show brain blood flow falling by around a quarter on standing, which explains the fog and the need to lie down.
• The immune system is stuck: natural killer cell function is reduced, and some people carry antibodies against the receptors that control blood vessels.
• The gut is involved: fewer butyrate-producing bacteria, and lower butyrate tracks with worse fatigue.

Common causes and triggers

In 30 years of practice, I've rarely seen ME/CFS appear out of nowhere. The load usually came first.

• Viral infection: glandular fever (EBV), influenza, Ross River virus and now COVID-19. Many people can date their onset to a specific illness.
• Mould and water-damaged buildings: in one study, 93% of 112 people with CFS had at least one mould toxin in their urine, and over 90% reported exposure to a water-damaged building. The study's control group has been criticised, so treat it as an association, but in clinic a mouldy home is one of the most common hidden drivers.
• Chemical exposure: pesticides, solvents, salon chemicals, renovation and fragrance. Some insecticides and fungicides directly block part of the mitochondrial energy chain.
• Heavy metals: mercury, lead and cadmium bind the sulphur groups enzymes need and drain glutathione.
• Surgery, anaesthetic and certain medicines: fluoroquinolone antibiotics, statins (lower CoQ10) and regular paracetamol (lowers glutathione).
• Major stress or overtraining: years of running on empty before the trigger.

Chronic fatigue and nitric oxide: the delivery problem

Repaired mitochondria still need oxygen and fuel delivered. That delivery depends on nitric oxide from the lining of your blood vessels. NO relaxes the vessel, increases blood flow to working muscle and brain, and matches supply to demand. In ME/CFS this system is consistently impaired.

• Half have measurable endothelial dysfunction. In a Berlin study of 35 people with ME/CFS, 51% had peripheral endothelial dysfunction against 20% of healthy controls. Those with it had more severe disease and more immune symptoms.
• Large and small vessels are both affected. A Norwegian study found reduced flow-mediated dilation (large arteries) and reduced post-occlusive hyperaemia (small vessels). A follow-up measured FMD at 5.1% in ME/CFS against 8.2% in healthy people. Crucially, the vessels relaxed normally when given a nitrate drug, which points to the problem being the endothelium's own NO supply, not the muscle of the vessel wall.
• Something in the blood suppresses NO. When healthy endothelial cells were bathed in plasma from people with ME/CFS, they produced significantly less NO, and their NO enzyme (eNOS) was switched towards its "off" state.
• Long COVID looks the same. A 2023 study found people with long COVID and ME/CFS had similarly impaired vascular function, with no difference between the two groups.

Why healthy nitric oxide falls in ME/CFS

• Oxidative stress: free radicals destroy NO and "uncouple" the NO enzyme so it makes more free radicals instead.
• Immune activation and autoantibodies: inflammatory signals and antibodies against vessel receptors disturb blood flow regulation.
• Low glutathione: the chemical load spends the antioxidants that would otherwise protect NO.
• Reduced movement: shear stress from blood flow is a key NO trigger, and crashes force inactivity.
• Age: by around 40, most adults make roughly half the nitric oxide they did at 20.

Restore it carefully

Under heavy oxidative stress, NO can combine with free radicals to form peroxynitrite, a theory long discussed in ME/CFS and chemical sensitivity. So the aim is a restored baseline of healthy, vessel-lining NO with antioxidant cover, introduced slowly, not a flood of NO into an inflamed system.

Detoxification without the crash

Chemical load and mitochondria are locked in a loop. The more load, the more glutathione is spent clearing it, the less is left to protect the mitochondria and NO, and the less energy there is to run detoxification. You can't rest your way out of the load. You break the loop at the start, by removing exposures.

Lower the load first

• Work through your home room by room, starting with the bedroom: mould, gas cooking without a rangehood, air fresheners, scented candles and new furniture off-gassing.
• Look at your work and hobbies: salon, cleaning, farming, painting, renovation, dry-cleaning, resin and 3D printing.
• Retire antiseptic mouthwash, synthetic fragrance and aerosols.
• Filter your drinking water, cook and store in glass or steel, and choose organic for the most sprayed produce.

Open the exits gently

1. Bowel: one to two soft motions daily before anything else. Toxins in bile are reabsorbed if the bowel is slow.
2. Fluid and a pinch of salt: low blood volume is common in ME/CFS. Around 30 ml of water per kg with a pinch of sea salt in the morning glass (skip the salt with high blood pressure or kidney disease).
3. Liver through food: broccoli sprouts, garlic, onion, beetroot and bitter greens.
4. Glutathione: NAC from 300 mg a day, building to 600 mg twice daily over two to three weeks, plus glycine 3 g at night.
5. Binders only if needed: where mould or a heavy exposure is confirmed, charcoal, bentonite or chlorella, two hours away from food and medicine.

Headache, flu-like aching, deeper fog or a crash lasting more than two days means you're moving too fast. Drop back a step and wait a week.

Medicinal mushrooms for chronic fatigue

Medicinal mushrooms have been used for exhaustion and recovery for more than 2,000 years in Chinese medicine. For ME/CFS they bring three things: immune balance, energy and calm.

Reishi (Ganoderma lucidum)

In a randomised, double-blind trial of 132 people with neurasthenia, a condition defined by fatigue, poor wellbeing and irritability, a reishi polysaccharide extract was significantly better than placebo. A smaller Thai trial in chronic fatigue syndrome reported lower fatigue and better quality of life over 12 weeks. A University of Hong Kong trial of a reishi supplement in ME/CFS and post-COVID fatigue has finished recruiting, and results are expected.

Cordyceps

Traditionally the mushroom for stamina, breathlessness and recovery. In a placebo-controlled trial, a cordyceps blend at 4 g a day for three weeks improved maximal oxygen uptake by 4.8 ml/kg/min and extended time to exhaustion by about 70 seconds. Lab research suggests it raises cellular ATP production and switches on AMPK, the same energy switch berberine works on.

Lion's mane

Supports nerve growth factor and has been studied for low mood and anxiety, both common after years of illness. A good fit where brain fog leads.

Chaga, shiitake and turkey tail

Beta-glucans and antioxidants that support natural killer cell activity and immune balance, which matters where a virus started it.

BOOST combines seven medicinal mushrooms, including cordyceps, reishi, lion's mane and chaga, with spirulina, chlorella, wheatgrass, moringa and broccoli sprout. In ME/CFS I add it at half a serve from week six, once the bowel is moving and you're not crashing. Skip it if mushrooms or algae don't suit you.

Rebuilding the engine

Only once the load is coming down and the exits are open. One nutrient every three to five days, at a quarter to half dose for three days first.

• Tier 1 (from week 4): magnesium glycinate or malate, ubiquinol (CoQ10) 200 mg, an activated B complex with B1 and B2, omega-3, vitamin D3 and vitamin C. CoQ10 with NADH has been studied in ME/CFS fatigue.
• Tier 2 (from week 6): D-ribose, acetyl-L-carnitine, creatine and taurine.
• Tier 3 (from week 8): NADH, PQQ, alpha-lipoic acid, methylfolate and B12, started low.
• Pace everything: use 60 to 70% of the energy you think you have, work in 15 to 20 minute blocks, and treat a morning HRV well below your average as a rest day.

Ultimate 4: delivery, protected

Ultimate 4 is the tool I use for the delivery side of the problem. It supports both of the body's nitric oxide pathways and protects NO once it's made.

• Beetroot (1,200 mg) and rocket (1,200 mg): dietary nitrate, the pathway that still works when the vessel enzyme is strained, which is exactly the situation the ME/CFS research describes.
• L-citrulline (1,620 mg): raw material for the enzyme pathway, gentler than arginine.
• Vitamin C (600 mg) and hibiscus: protect NO from free radicals; vitamin C also recycles glutathione.
• Glycine (600 mg): feeds glutathione, your main detox antioxidant.
• Taurine (360 mg) and magnesium taurate: protect mitochondria and support every ATP molecule.

For sensitive systems, start at a quarter to half a scoop and build to one scoop over one to two weeks. Add nitrate foods daily, and hum for five minutes a day: nasal NO rises and the vagus nerve settles. Test with a saliva strip first so you have a baseline.

Learn more about Ultimate 4 · Nitric Oxide Test Strips · BOOST

My 12-week approach at a glance

• Weeks 0 to 1: find your energy envelope. Daily scores, morning HRV, saliva NO strip, a 10-minute stand test.
• Weeks 1 to 4: the hidden load audit, one exposure a week.
• Weeks 3 to 8: open the exits: bowel, fluid and salt, then NAC and glycine.
• Weeks 4 to 12: Tier 1 nutrients one at a time. Ultimate 4 from a quarter scoop. Slow breathing at six breaths a minute, twice daily.
• Weeks 6 to 12: Tiers 2 and 3, BOOST at half a serve, one herb for whatever is leading. Movement only after two to three weeks without a major crash. Retest at week 12.

Most people notice the first shift at six to eight weeks: fewer crashes, better sleep, a clearer head. Mitochondrial repair takes three to six months, and progress is rarely a straight line. The full plan with the hidden load audit and tracker is in The Butterworth Protocols.

What the science does and doesn't show yet

Endothelial dysfunction in ME/CFS has now been shown by several independent groups using different methods, though not in every patient and not in every study. The lab finding that ME/CFS plasma suppresses NO is striking but small. There are no published trials yet of nitrate or citrulline supplements in ME/CFS, and the mushroom trials are modest in size. The direction of the evidence is clear enough to act on carefully, and testing lets you see whether your own levels respond.

Frequently asked questions

Is chronic fatigue syndrome linked to low nitric oxide?

Several studies show reduced endothelial function, a marker of vessel-lining nitric oxide, in ME/CFS, and plasma from people with ME/CFS reduced NO production in lab studies.

Can detoxing make chronic fatigue worse?

Yes, if it's done too fast. Remove exposures first and open the bowel, liver and kidneys before using anything that mobilises stored chemicals.

Which mushroom is best for fatigue?

Cordyceps for stamina and oxygen use, reishi for immune balance, sleep and wellbeing. Many people do best on a blend.

Should I exercise with ME/CFS?

Not by pushing through. Movement comes back only once your baseline is stable, starting with five minutes lying or seated and adding one to two minutes a week if there is no crash 24 to 72 hours later.

How do I know if my nitric oxide is low?

A saliva test strip gives an at-home reading in about 15 seconds. Learn how to test and optimise your nitric oxide.

Living with ME/CFS? Join the conversation in our Butterworth Health Optimisation community.

Jeff Butterworth N.D. Specialist Naturopath, 30 years in clinical practice

References

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• NICE guideline NG206. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. 2021.

This article is for general education and is not a substitute for individual health advice. Supplements support healthy function; they do not treat, cure or prevent any disease. Always read the label and follow the directions for use. Keep taking your prescribed medication.