Fatigue can feel like a battery that will not hold a charge. You sleep, you eat, you rest, and you still run out by mid afternoon. That is a useful image, because a lot of fatigue is, at root, an energy problem. Your cells make ATP in mitochondria, and if that system is slow, everything downstream feels slow.

That does not mean a mitochondrial supplement will fix it. It means the mechanism is worth checking, one piece at a time, with the trials that actually exist.

CoQ10 sits in the electron transport chain, shuttling electrons through complexes I, II and III. It is also an antioxidant. Blood and cell levels are lower in ME/CFS than in controls, which is why researchers tested it there.

The best trial is Castro-Marrero and colleagues, 2015. Seventy three Spanish patients with chronic fatigue syndrome took 200 mg CoQ10 plus 20 mg NADH daily for eight weeks. Fatigue scores fell, cellular ATP rose, and antioxidant markers improved compared with placebo. A follow up of 207 patients over 12 weeks found less cognitive fatigue and better sleep quality than placebo, though overall quality of life did not separate. Effects were modest, and the trials used the combination, so CoQ10 alone is less well tested. A separate trial in healthy volunteers found 300 mg a day reduced subjective fatigue during eight days of activity induced exhaustion, while 100 mg a day did not. Doses in research usually run 100 to 400 mg daily. CoQ10 can interact with warfarin and blood pressure drugs, so check first, especially if you are on a statin. Statins lower CoQ10, which is one reason some people on statins feel achy and tired, though that does not prove CoQ10 will fix it.

NADH is the reduced form of NAD+, the coenzyme that carries energy from food to ATP production. In a four week crossover trial of 26 ME/CFS patients, 10 mg oral NADH produced a meaningful improvement in 31 percent versus 8 percent on placebo. A 2004 trial found it compared well with conventional management over the first months. The two larger Spanish trials combining 20 mg NADH with CoQ10 reduced fatigue over 8 to 12 weeks. Studied dose is 10 to 20 mg stabilized oral NADH on an empty stomach each morning. NAD+ precursors such as NMN and nicotinamide riboside have not been tested in ME/CFS, so do not swap them in and assume the same result.

Acetyl-L-carnitine carries fatty acids into mitochondria, where they are burned for fuel. Several studies have found low serum or muscle acylcarnitine in ME/CFS. In an eight week comparison of 30 patients, 3 g L-carnitine daily improved 12 of 18 clinical measures while the comparison drug amantadine was poorly tolerated. A 24 week open label study of 90 patients found 2 g acetyl-L-carnitine improved mental fatigue and 2 g propionyl-L-carnitine improved general fatigue in about 60 percent of patients, but the combination did worse. With no placebo controlled trial, the evidence is preliminary. Studied dose is 2 g acetyl-L-carnitine or 2 to 3 g L-carnitine daily in divided doses with meals for 8 to 24 weeks. The acetyl form crosses the blood brain barrier more readily than plain L-carnitine, which may explain why people report mental clarity as well as physical energy. It can upset the stomach and can interact with thyroid medicine and blood thinners.

D-ribose is a sugar that forms the structural backbone of ATP itself. Taking it bypasses a rate limiting step and provides a shortcut to rebuild ATP pools. That matters most after intense exercise or in conditions where ATP pools have been depleted, like heart disease or chronic fatigue. In an open label study, 41 patients took 5 g three times daily for three weeks and reported better energy, sleep, mental clarity, pain intensity and wellbeing. Open label means no placebo group, so expectation could explain a lot of that. D-ribose can lower blood sugar, so people on diabetes medicine need a clinician check, and it is not a daily energy drink. I would put it in the short trial category, three weeks, one metric, then stop if nothing changes.

Creatine is the fastest ATP buffer. It maintains a reserve of phosphocreatine, which donates a phosphate group to spent ATP, called ADP, to regenerate it almost instantly. Dietary creatine at 5 to 20 g a day raises muscle creatine, with improvements in anaerobic performance after about two weeks. For fatigue, the signal is strongest under metabolic stress, sleep deprivation, high cognitive load, or ageing. A 2024 meta analysis of 16 trials, 492 people, found creatine improved memory and processing speed, with no clear effect on overall cognition. In women with fibromyalgia, creatine improved muscle strength, functional capacity, and muscle bioenergetics in a randomised trial. Usual dose is 3 to 5 g of creatine monohydrate a day. It helps with short, high demand tasks. It will not do much for endurance or for general low energy, because those rely on mitochondria making ATP from oxygen and fuel over longer periods. Creatine is not a substitute for sleep.

Magnesium belongs in this piece too, because ATP must be bound to magnesium to function. Magnesium shields the negative charges on ATP, allowing it to interact with enzymes and transfer energy. Without magnesium, ATP dependent enzyme activity almost stops in lab experiments. Most adults need 300 to 400 mg a day from all sources combined. Magnesium glycinate and citrate are well absorbed forms. The European Food Safety Authority allows a claim that magnesium contributes to normal energy yielding metabolism and to the reduction of tiredness and fatigue, which is a label claim, not proof it will fix your fatigue if you are already sufficient.

Alpha-lipoic acid is a mitochondrial dehydrogenase cofactor, and it also recycles other antioxidants. A fibromyalgia trial showed some benefit, but the human data for fatigue specifically is thin. I would put it in the same bucket as CoQ10, plausible, small trials, worth a conversation if you have nerve pain or blood sugar issues as well, not as a first line for fatigue alone.

How I would use this, if labs were already checked and normal, is to pick one energy bottleneck and test it for 8 to 12 weeks. If your fatigue is worst after exertion and you crash the next day, start with CoQ10 plus NADH, the combination with the best trial data in ME/CFS. If your fatigue is mental, with word finding trouble, start with acetyl-L-carnitine. If your fatigue is muscle weakness and you are older or eat little meat, start with creatine. Do not start all four at once. You will not know what worked, and you will increase the chance of an interaction. Track one thing, like steps, or hours until your afternoon crash, or a fatigue score from 0 to 10 each evening. Stop what does not move that number in 8 weeks.

Post exertional malaise, where exertion makes you worse for a day or more, is different from ordinary tiredness. If you have that, pacing matters more than any supplement, and pushing through will make you worse. Talk to a clinician who knows ME/CFS or long COVID before you try an energy stack.

This is education, not medical advice. It is not a diagnosis, and it does not replace professional care.

Sources: Castro-Marrero and colleagues, Antioxidants and Redox Signaling, 2015. Physiology, Bethesda, 2025, mitochondrial dysfunction in ME/CFS. Xu and colleagues, Frontiers in Nutrition, 2024.