Fatigue is tiredness that rest does not fix, with crashes after exertion, fog, and low stamina. It can come from low iron, low B12, thyroid trouble, bad sleep, or post viral fatigue. If it is new, persistent, or getting worse, see a clinician first. This piece is not about those causes. It is about the experimental corner, where people are using compounds off label because the pharmacology makes sense on paper.

Off label here means a compound was studied or sold for one thing, and people are now using it for fatigue because of how it works in the body. That is a theory. A theory is not a trial. I will say which part is mechanism, which part is animal data, and which part is an actual human trial, for each one. If the human trial is small or missing, I will say so. I am not telling you to take these.

I sort fatigue into bottlenecks, because that is how you decide which experimental idea even fits. Low fuel, low transmitter, slow membrane repair, low energy, and inflammation or oxidative stress. Most common supplements fix fuel. Most experimental ones try to fix energy or cleanup. That is why they sound exciting, and why they often disappoint in healthy people who do not have that bottleneck.

PQQ, pyrroloquinoline quinone, is a redox cofactor that in cell studies activates CREB and PGC-1 alpha and increases mitochondrial biogenesis, the creation of new mitochondria. In people, the trials are small and Japanese. Itoh and colleagues, 2016, 41 healthy older adults, 20 mg a day for 12 weeks, limited the decline in Stroop attention performance. Shiojima and colleagues, 2022, 64 healthy adults aged 40 to 79, 12 weeks of PQQ, improved memory, attention, reaction time and cognitive flexibility. A 2024 trial of a hydrogen plus PQQ blend improved orientation in older adults with mild cognitive impairment, but the blend means you cannot isolate PQQ. No human trial has shown PQQ actually increases mitochondrial density in the brain. It measures test scores, not mitochondria. So call it promising, not proven. Do not count on it as a standalone fix. Studied dose is 20 mg a day. It pairs in marketing with CoQ10, because CoQ10 optimises existing mitochondria while PQQ is supposed to make new ones. In rats, the combination did no better than PQQ alone. In people, the synergy claim rests on a 2024 review of Japanese studies, not on a large trial.

NMN and NR, nicotinamide mononucleotide and nicotinamide riboside, are NAD precursors. NAD is a coenzyme involved in virtually every energy producing reaction in the cell, and NAD falls with age. NMN and NR raise NAD in blood, reliably. Animal data was dramatic, reversing muscle wasting, improving insulin sensitivity, restoring fertility in aged female mice. Human trials are showing safety and bioavailability, with some improvements in muscle function, physical endurance, and metabolic markers. The honest picture is, NAD precursors are likely beneficial, especially over 40, but the human data does not yet replicate the spectacular results seen in mice.

A recent open label study in 42 healthy adults aged 45 to 65, NMN alone and NMN in multi ingredient formulas for 42 days, found no statistically significant improvements in cardiopulmonary or cognitive function, the primary objectives. The multi ingredient group did a bit better on memory, but not significantly. A large long trial in Parkinson's disease found no benefit from NR. That does not kill the idea, it just says the mechanism is strong and the fatigue benefit is unproven. Studied dose is NMN 250 to 500 mg a day, NR 300 to 1,000 mg a day, both in the morning. Avoid NMN or NR if you have active cancer without medical guidance, because NAD pathways are involved in cell growth as well as repair, and that is a conversation for an oncologist, not a supplement blog.

Spermidine is a polyamine that triggers autophagy, the cell's cleanup process. Higher dietary spermidine intake is associated with lower cardiovascular mortality and better cognitive ageing in observational data. A 2021 trial in older adults with subjective cognitive decline found spermidine improved memory consolidation versus placebo. That is one trial, and it is interesting because the mechanism, clearing damaged mitochondria and proteins, fits fatigue after viral illness or poor sleep. It does not prove spermidine fixes fatigue in a healthy 35 year old. Food sources are wheat germ, soy, mushrooms, and aged cheese. Supplement doses in trials are usually around 1 to 2 mg a day, though products vary widely. If you try it, give it 8 to 12 weeks and track one metric, like steps or afternoon crash frequency.

Urolithin A triggers mitophagy, a more specific cleanup of damaged mitochondria. It is made in the gut from ellagitannins in pomegranate, walnuts, and berries, but only some people make it well from food. A 2022 trial published in Nature Metabolism found urolithin A, 500 to 1,000 mg a day, improved muscle endurance in middle aged adults by 10 to 12 percent. Muscle is not brain, and muscle endurance is not fatigue, but the pathway is shared, and that is exactly the kind of first principles leap you should label as a leap, not as proof. If your fatigue is muscle weakness and poor exercise tolerance, urolithin A is more plausible than if your fatigue is mental and sleep driven.

GlyNAC is glycine plus N-acetyl cysteine, combined to raise glutathione. Glutathione is the brain and body's main antioxidant, and cysteine is the rate limiting building block for making it. Glycine is the other building block. In older adults, GlyNAC improved glutathione levels, mitochondrial function, and some measures of physical function in small trials. In ME/CFS and fibromyalgia, a 2026 narrative review in Nutrients distinguished mechanistic plausibility from clinical efficacy, and said disease specific randomised evidence remains limited for GlyNAC. That is the right framing. The mechanism is clean, the human fatigue trials are small and short. Studied doses are usually glycine 100 mg per kilo plus NAC 100 mg per kilo, which is a lot, and NAC can upset the stomach and interact with nitroglycerin. Do not start GlyNAC if you take blood pressure medicine without a clinician check.

Taurine stabilises mitochondrial membranes and modulates calcium homeostasis, supporting neuromuscular function. Its clearest use is the rare disease MELAS, a mitochondrial disorder, where taurine is used at high doses under medical supervision. A 2025 study found blood taurine levels do not fall with age in the way earlier work suggested, which weakens the simple deficiency story. For ordinary fatigue, taurine is plausible, cheap, and thin on human trials. I would put it in the maybe pile if you have muscle cramps and poor exercise tolerance, not as a first line for mental fatigue.

Alpha-lipoic acid is a mitochondrial dehydrogenase cofactor, and it recycles other antioxidants like glutathione and vitamin C. A fibromyalgia trial showed some benefit, but the human data for fatigue specifically is thin. It can lower blood sugar, so people on diabetes medicine need a check. It is not a daily energy pill.

Two compounds I am leaving out on purpose, even though people ask about them. Methylene blue can interact dangerously with SSRIs and cause serotonin syndrome, and the human cognition trials are few and small. It also turns urine blue and can cause haemolysis in people with G6PD deficiency. Lithium orotate is sold as a low dose mood supplement, but lithium has a narrow safety window, interacts with kidney function, thyroid, and diuretics, and needs blood monitoring even at low doses. First principles does not make a risky compound safe.

Low dose naltrexone is a prescription drug, not a supplement, and I want to be clear about that boundary. It is used off label at 1 to 4.5 mg at night for ME/CFS and fibromyalgia, on the theory that it briefly blocks opioid receptors and then rebounds, modulating inflammation and endorphins. Small trials and case series report less fatigue and pain in some people, with vivid dreams and sleep disruption as common side effects. It needs a prescription, a clinician who knows ME/CFS, and a discussion about opioids, alcohol, and liver function. Do not buy it online and do not take it as a supplement. I mention it here only so you know what the theory is, not as a recommendation.

Oxaloacetate is another experimental TCA cycle substrate, like D-ribose and carnitine. It feeds directly into the Krebs cycle, which is the core energy pathway. In ME/CFS trials, oxaloacetate improved fatigue, exercise performance, mental clarity, pain, and sleep quality in small studies, but the trials are small and not yet replicated in large groups. It is expensive, it needs to be taken on an empty stomach, and it can lower blood sugar. I would put it in the same bucket as D-ribose, interesting, early, worth a clinician conversation if you have post exertional malaise, not a first try.

How would I use all of this, if labs and sleep were already checked and normal? I would pick one bottleneck, not five supplements at once. If your fatigue is muscle weakness and poor exercise tolerance, try CoQ10 plus carnitine first, the combination with the best trial data in ME/CFS. If your fatigue is mental, with fog and word finding trouble, try PQQ or citicoline, not NMN plus spermidine plus urolithin A all at once. If your fatigue follows a virus and tracks with inflammation, try GlyNAC or curcumin, and check hs-CRP first. Give each one 8 to 12 weeks, except acute ones like caffeine which you judge in hours. Stop what does not move one metric, like steps, or hours until your afternoon crash, or a fatigue score from 0 to 10 each evening. Keep what does, and check interactions before you add the next one.

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. Experimental and off label use, especially for NMN, PQQ, spermidine, and any mitochondrial stack, needs a clinician conversation first, especially if you take prescription medicine, are pregnant, or have kidney, liver, thyroid, or heart issues.

Sources: Castro-Marrero and colleagues, Antioxidants and Redox Signaling, 2015. Physiology, Bethesda, 2025, mitochondrial dysfunction in ME/CFS. Nutrients, 2026, micronutrition for mitochondrial dysfunction in ME/CFS and fibromyalgia. Itoh and colleagues, 2016. Shiojima and colleagues, 2022.