Long COVID and Nitric Oxide: Causes and How to Detoxify

Short answer: long COVID is, at its core, a blood vessel and energy problem. The virus targets the lining of the blood vessels, and months later many people still show reduced nitric oxide function, tiny clots in the circulation, reactivated old viruses and stressed mitochondria. The encouraging part: in a randomised trial, restoring the nitric oxide pathway with L-arginine and vitamin C for just 28 days improved walking distance, grip strength, blood vessel function and fatigue. Add a lower toxic load and medicinal mushrooms for immune balance, and you have a practical plan.

Key takeaways

• Long COVID follows at least 10% of infections, has over 200 recorded symptoms and affects an estimated 65 million people or more worldwide.
• COVID-19 is increasingly understood as a disease of the blood vessel lining. Oxidative stress and reduced nitric oxide were found in patients from the acute phase.
• Months later, people with long COVID show impaired flow-mediated dilation, a marker of nitric oxide function, at levels similar to ME/CFS.
• In a 50-person randomised trial, an NO-pathway supplement (L-arginine plus vitamin C) left just 2 people in the active group still fatigued at day 28, against 21 on placebo.
• Common drivers include viral persistence, Epstein-Barr virus reactivation, microclots, immune activation and a body already carrying a heavy load.

What is long COVID?

Long COVID (post-COVID-19 condition) is ongoing illness after a COVID-19 infection, lasting months or years. The most common symptoms are fatigue, post-exertional crashes, brain fog, breathlessness, a racing heart on standing, poor sleep, muscle and joint pain, and changes in smell and taste.

It is not limited to people who were very sick. Most cases follow a mild infection, and the highest rates of diagnosis are in people aged 36 to 50, right in the middle of working and family life. Many people with long COVID meet the criteria for ME/CFS, and the research on the two conditions now overlaps heavily.

The common causes of long COVID

Long COVID likely has several overlapping causes, and different people lean towards different ones. The leading mechanisms are:

• Viral persistence: fragments of the virus or its proteins can linger in tissues such as the gut for months, keeping the immune system activated.
• Reactivated old viruses: in one study, 67% of people with long COVID showed signs of Epstein-Barr virus (glandular fever) reactivation, against 10% of those who recovered fully. HHV-6 and other herpes viruses are also involved.
• Microclots: South African researchers found tiny clots resistant to the body's normal clot breakdown in the blood of people with long COVID, alongside overactive platelets. These can block capillaries and limit oxygen delivery.
• Blood vessel lining damage: the virus binds to ACE2 receptors on the endothelium, the cells that make your nitric oxide.
• Immune dysregulation and autoimmunity: altered T cells, activated B cells and, in some people, autoantibodies.
• Mitochondrial stress: after exercise, muscle biopsies in long COVID with post-exertional malaise show mitochondrial dysfunction and tissue damage.
• Gut microbiome changes: loss of beneficial bacteria and a leakier gut lining.
• The load that was already there: in clinic I see the same pattern as chronic fatigue. Mould, chemical exposure, poor sleep, high stress, metabolic problems or low nutrient status before the infection. COVID was the last straw on a loaded system.

Long COVID and nitric oxide

Nitric oxide (NO) is made by the cells lining your blood vessels. It relaxes vessels, delivers oxygen to muscle and brain, keeps platelets from sticking and helps calm inflammation. It is also one of the immune system's own antiviral tools. In laboratory studies, nitric oxide reduced replication of both the original SARS coronavirus and SARS-CoV-2, partly by blocking an enzyme the virus needs to copy itself.

Here is how COVID-19 drives nitric oxide down:

• During infection: a 2022 study in hospitalised COVID-19 patients found a sharp rise in oxidative stress alongside reduced nitric oxide bioavailability, and concluded this was a likely driver of endothelial dysfunction.
• Months later: people with long COVID show reduced flow-mediated dilation, the standard measure of how well the artery lining responds with NO. One study measured 8.2% in long COVID against 10.3% in the comparison group. A 2023 study found long COVID and ME/CFS had similarly impaired vascular function.
• Symptom severity: a 2025 study found that lower nitric oxide metabolites and lower antioxidant levels helped predict the severity of fatigue, mood and physical symptoms in long COVID.
• Microclots and platelets: healthy NO is one of the body's main brakes on platelet stickiness. Less NO, more sticky platelets, more microclots, less oxygen to tissue.

The trial that matters most

Researchers in Rome ran a randomised, placebo-controlled trial in 50 adults with long COVID and persistent fatigue. The active group took 1.66 g of L-arginine with 500 mg of liposomal vitamin C twice daily for 28 days, a combination designed to feed and protect the nitric oxide pathway.

• Six-minute walk distance improved by 30 metres in the active group and not at all on placebo.
• Hand grip strength rose by 3.4 kg against 1.0 kg.
• Flow-mediated dilation was 14.3% in the active group against 9.4% on placebo.
• At day 28, only 2 people in the active group still reported fatigue, against 21 in the placebo group.

It was a single-blind trial and a small one, so it needs repeating. But it is one of the clearest positive results in long COVID, and it points straight at the nitric oxide pathway.

Restore it, protected

Long COVID carries heavy oxidative stress. Under those conditions NO can combine with free radicals to form peroxynitrite. That is why vitamin C was part of the trial, and why I always restore NO with antioxidant cover, starting gently.

Detoxification after COVID

The immune system's fight with the virus burns through glutathione, the body's main detox antioxidant. Many people with long COVID then become newly sensitive to perfume, petrol, cleaning sprays or alcohol. That sensitivity is a sign of a loaded system.

Lower the load

• Check your home for mould, especially the bedroom, bathroom and air-con units. A mouldy home keeps the immune system switched on.
• Go fragrance-free: air fresheners, plug-ins, scented candles, perfume and laundry fragrance.
• Ventilate gas cooking, or use the rangehood every time.
• Retire antiseptic mouthwash so mouth bacteria can turn dietary nitrate into nitric oxide.
• Cut alcohol completely while you recover. It drains glutathione and disrupts sleep.

Open the exits gently

1. Bowel: one to two soft motions daily, with magnesium citrate, ground flaxseed or psyllium and plenty of vegetables.
2. Fluid and salt: 2 to 3 litres of fluid with a little extra salt helps if standing makes you worse (unless you have high blood pressure or kidney disease).
3. Glutathione: NAC, starting at 300 mg and building to 600 mg twice daily, with glycine 3 g at night. NAC was widely studied during the pandemic for its antioxidant and mucus-thinning effects.
4. Liver through food: broccoli sprouts (sulforaphane switches on the body's own detox and antioxidant genes), garlic, beetroot, bitter greens and lemon.
5. Lymph and sweat: dry brushing, legs up the wall, and short low-heat sauna only once crashes have settled.

Medicinal mushrooms for long COVID

Medicinal mushrooms suit long COVID because so much of it is immune: a virus that hasn't fully cleared, old viruses reactivated, and an immune system that can't settle.

Reishi

The immune-balancing mushroom, used for more than 2,000 years for recovery, sleep and calm. In a 132-person randomised trial, a reishi extract improved fatigue-type symptoms and wellbeing more than placebo. A University of Hong Kong trial is now testing a reishi supplement specifically in post-COVID fatigue and ME/CFS.

Cordyceps

Traditionally used for breathlessness and stamina, which makes it a natural fit for post-COVID breathlessness and exercise intolerance. In a placebo-controlled trial, a cordyceps blend at 4 g a day improved maximal oxygen uptake and time to exhaustion after three weeks.

Lion's mane

Supports nerve growth factor, studied for mood and anxiety. Brain fog and low mood are among the most common long COVID complaints.

Turkey tail, shiitake and chaga

Beta-glucans that support natural killer cell activity, the part of the immune system that keeps viruses like EBV in check, plus antioxidant cover.

BOOST combines seven medicinal mushrooms, including reishi, cordyceps, lion's mane and chaga, with spirulina, chlorella and broccoli sprout. I introduce it at half a serve once the bowel is moving and crashes have settled, then build to a full serve. Skip it if mushrooms or algae don't suit you.

Rebuilding energy and calming the system

• Pace: post-exertional malaise is common in long COVID. Use 60 to 70% of the energy you think you have, and treat a low morning HRV as a rest day.
• Mitochondrial nutrients, one at a time: magnesium, CoQ10 (ubiquinol), an activated B complex, omega-3, vitamin D and vitamin C, then D-ribose, carnitine and creatine.
• Nitrate foods daily: beetroot, rocket, celery and lettuce.
• Breathe through your nose and hum: the sinuses make nitric oxide, and humming raises nasal NO many times over while settling the vagus nerve. Breathing at six breaths a minute for 10 minutes twice daily helps calm a racing heart.
• Morning daylight and early nights: to reset sleep and the stress axis.

Ultimate 4: the nitric oxide foundation

The Rome trial used arginine and vitamin C. I formulated Ultimate 4 to go further: both of the body's nitric oxide pathways, with the antioxidant protection a post-viral system needs.

• L-citrulline (1,620 mg): the body converts citrulline to arginine, and it raises arginine levels more reliably than arginine itself, which is broken down heavily in the gut and liver.
• Beetroot (1,200 mg) and rocket (1,200 mg): dietary nitrate, the pathway that still works when the vessel lining is damaged.
• Vitamin C (600 mg): the same partner used in the trial. Protects NO and recycles glutathione.
• Glycine (600 mg), taurine (360 mg), magnesium taurate and hibiscus: glutathione support, mitochondrial protection and polyphenols that protect NO.

Start at a quarter to half a scoop if you're sensitive and build to one scoop over one to two weeks. Test your nitric oxide with a saliva strip before you start and again after a few weeks.

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

My long COVID plan at a glance

• Weeks 0 to 1: pace and baseline. Daily energy and sleep scores, morning HRV, a saliva NO strip, a 10-minute stand test.
• Weeks 1 to 4: lower the load, one exposure a week. Retire mouthwash, fragrance and alcohol.
• Weeks 2 to 6: open the exits and start Ultimate 4 from a quarter scoop, with nitrate foods daily and humming.
• Weeks 4 to 12: mitochondrial nutrients one at a time, then BOOST at half a serve. Gentle movement only after two to three weeks without a major crash.
• Week 12: retest your NO strip, HRV trend and scores.

Long COVID shares its biology with ME/CFS, so the full CFS/ME protocol in The Butterworth Protocols applies, including the hidden load audit and 12-week tracker. You can also read my article on chronic fatigue syndrome.

What the science does and doesn't show yet

Endothelial dysfunction in long COVID is well documented. The arginine plus vitamin C trial is small and single-blind. A US trial of nitrate-rich beetroot juice in long COVID has finished, and I'll share the results when they're published. The mushroom evidence in long COVID itself is still emerging; the trials so far are in fatigue and exercise more broadly. Long COVID is still being defined, and different people have different drivers, which is why testing and pacing matter so much.

Frequently asked questions

Does COVID lower nitric oxide?

Studies show reduced nitric oxide bioavailability during COVID-19 and impaired endothelial function, a marker of NO, months after infection in people with long COVID.

Can L-arginine help long COVID?

A randomised trial found L-arginine with vitamin C for 28 days improved walking distance, strength, blood vessel function and fatigue in adults with long COVID. L-citrulline raises arginine more reliably than arginine itself.

Is long COVID the same as chronic fatigue syndrome?

Not exactly, but many people with long COVID meet ME/CFS criteria, and studies show similar blood vessel and energy changes in both.

Which mushrooms help after COVID?

Reishi for immune balance and recovery, cordyceps for breathlessness and stamina, lion's mane for brain fog and mood, and turkey tail for immune support.

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.

Recovering from long COVID? 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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• Tosato M, et al. Effects of L-arginine plus vitamin C supplementation on physical performance, endothelial function, and persistent fatigue in adults with long COVID: a single-blind randomized controlled trial. Nutrients. 2022;14(23):4984.
• Calvani R, et al. Effects of L-arginine plus vitamin C supplementation on L-arginine metabolism in adults with long COVID: secondary analysis of a randomized clinical trial. International Journal of Molecular Sciences. 2023;24(6):5078.
• Montiel V, et al. Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients. eBioMedicine. 2022;77:103893.
• McLaughlin M, et al. People with long COVID and ME/CFS exhibit similarly impaired vascular function. University of Salford, 2023.
• Maes M, et al. The physio-affective symptoms of long COVID are strongly predicted by the severity of the acute infectious phase, and lowered antioxidant, nitric oxide, and alanine transaminase levels. medRxiv preprint. 2025.
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• Nitrite Supplementation in Long COVID Patients (beetroot juice), VA Pittsburgh. ClinicalTrials.gov NCT05618574.

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.