Supplements

How the energy supplements fit together

These supplements target different steps of the same energy pathway described in the “two engines”:

They don’t interfere with each other. They don’t add energy. They raise the point at which cells tip into the inefficient backup engine. From the inside, that feels like tasks costing less and crashes being smaller, not like having more in the tank.

What they won’t do: fix the immune or nervous-system problems behind the illness. They support the energy shortfall, not the cause.

Supplement by supplement

CoQ10 (ubiquinol) RCT

• What it does: carries electrons in the mitochondria and protects them from damage
• Evidence: Spanish trials (Castro-Marrero, 2015 and 2021, 73 and 207 people) of CoQ10 200 mg + NADH 20 mg found modest but significant reductions in fatigue over 8–12 weeks, with better sleep in the treated group.^1,2 People with ME/CFS tend to have lower CoQ10.³ Note: high-dose CoQ10 alone (500 mg) didn’t help in a Long COVID trial of 121 people.⁴
• Typical dose: 200 mg ubiquinol with a meal that contains fat (e.g. dinner)
• Cautions: generally well tolerated. It may interact with blood thinners like warfarin.

NADH RCT

• What it does: delivers the electrons CoQ10 carries. Low NAD⁺ is a suspected bottleneck in ME/CFS.
• Evidence: a 1999 crossover trial (10 mg/day, 26 people) found 31% responded on NADH versus 8% on placebo.⁵ The best evidence is the combination with CoQ10 above. The effect is “noticeably less bad”, not recovery.
• Typical dose: 20 mg on waking, on an empty stomach. Enteric-coated or sublingual forms absorb better, and stabilised forms last longer.
• Cautions: mildly stimulating, so it can cause insomnia if taken late.

NMN (NAD⁺ precursor) Hypothesis

• What it does: converts to NAD⁺ within hours, raising NAD⁺ more reliably than oral NADH
• Evidence: no ME/CFS trials (the trials used NADH). A reasonable alternative, but unproven.
• Typical dose: 250–500 mg each morning
• Cautions: take NADH or NMN, not both. Avoid combination products with green-tea extract or other stimulants.

Creatine monohydrate Adjacent field

• What it does: stores quick energy (phosphocreatine), buffering sudden demands like standing, stairs or a hard conversation without tipping into the backup engine
• Evidence: a small 6-month trial (12 people) of 4 g/day in post-COVID fatigue reduced fatigue, with measurable rises in brain and muscle creatine on scans.⁶ A creatine precursor improved muscle creatine and strength in women with ME/CFS, but not fatigue.⁷ In fibromyalgia, creatine improved strength but not pain.⁸
• Typical dose: 3–5 g daily with food. Skip the “loading phase” (it causes stomach upset and has no long-term advantage).
• Cautions: expect a 0.5–1 kg water-weight gain in the first fortnight. It raises serum creatinine slightly, so tell your GP. Check your kidney function is normal first. Check flavoured products for caffeine and stimulants. Plain monohydrate is safest.

Acetyl-L-carnitine (ALC) Open-label

• What it does: shuttles fuel into mitochondria. The acetyl form also reaches the brain and is used for brain fog.
• Evidence: small, mostly open-label trials from the 1990s and 2000s reported modest fatigue improvement.^9,10 Some studies have found lower carnitine-related compounds in ME/CFS blood.¹¹ A 2025 systematic review of supplements in ME/CFS rated the carnitine evidence as small and at high risk of bias.¹²
• Typical dose: 1–2 g daily in the morning for 8–12 weeks. One 500 mg capsule a day is under-dosed.
• Cautions: stomach upset, a fishy body odour. Take care with an underactive thyroid (it can blunt thyroid hormone), warfarin or a seizure history. Ideally test carnitine levels first.

Oxaloacetate RCT

• Evidence: the one supplement with a randomised trial in ME/CFS. 82 people took 2,000 mg/day for 3 months. It was well tolerated and reduced fatigue more than the control.¹³
• Cautions: the trial was industry-funded and led by an officer of the manufacturer, and it’s expensive (roughly US$300+ a month).

Quick comparison

Injectable carnitine

Injectable L-carnitine is popular in athletic circles, but there are no ME/CFS trials of it. All the positive trials used oral carnitine. In Australia, injectable carnitine is TGA-approved only for primary carnitine deficiency and dialysis. Off-label use needs a script and a compounding pharmacy, and a documented deficiency on blood tests is the practical prerequisite.

A sensible sequence: test your carnitine levels, then (if they’re low) try oral ALC for 8–12 weeks before considering injections.

Food first: red meat and cofactors

• Beef and lamb supply creatine, carnitine, well-absorbed iron, B12 and zinc. Three to four palm-sized portions a week, not overcooked, is a practical “whole food stack”. It supports supplements but doesn’t replace them.
• Your body makes its own carnitine using vitamin C and iron. Low ferritin can quietly cap production.
• If you don’t eat red meat, fish and eggs help, but you may need supplement doses of creatine and carnitine.

Iron, electrolytes and B12

• Iron: only if your stores are low. Alternate-day dosing absorbs better than daily, because a daily dose raises a hormone that blocks the next one.^14,15 Take it with vitamin C, away from tea and coffee, and at least 2 hours apart from electrolyte powders. Recheck levels after 3 months.
• Electrolytes and salt: only clearly useful if orthostatic intolerance is confirmed.
• B12: if active B12 and homocysteine are normal, extra B12 is unlikely to help.

How to tell if it’s working

What improvement looks like

Not “more energy”. Instead, a wider margin before a crash, and smaller crashes:

• The afternoon slump comes later or is milder
• A task that used to trigger a crash stops reliably doing so
• Crashes last one day instead of two or three
• Brain fog lifts earlier in the morning
• Standing and walking feel less like wading through sand
• Sleep feels deeper. This often improves first.

Most people who respond notice it in hindsight: “that stretch was less bad”. It’s rarely a moment where something switches on.

Timeline

• Weeks 1–3: possibly nothing
• Weeks 3–6: the first window where a real change is plausible
• Weeks 6–12: steady state. Judge at 12 weeks.

Doing it properly

1. Record the start date of each supplement.
2. Start one at a time, a couple of weeks apart. If you start several at once, you can’t tell which is working.
3. Keep your activity steady. Don’t spend improvements (see the good-day trap).
4. After 8 weeks, compare averages against your first fortnight.
5. If nothing has changed by week 12, stop them one at a time. A clear “no effect” is useful: it suggests energy production isn’t your main bottleneck right now.