Mitochondrial dysfunction
Impaired cellular energy production, proposed to underlie fatigue and post-exertional symptoms.
Impaired mitochondrial energy production is a plausible driver of fatigue and exertional symptoms, with objective signals on 31-P MRS (slowed phosphocreatine recovery). But the therapeutic story is weak: rigorous trials of CoQ10, NAD+ precursors (NR), oxaloacetate, and AXA1125 all missed their primary endpoints. Several popular supplements (urolithin A, NMN, MitoQ) have no Long COVID trial at all. The best dataset signal in this space was L-arginine plus vitamin C, but only in a single-blind study needing replication. Costs are non-trivial and largely out-of-pocket.
How it's tested
31-P MRS muscle spectroscopy
Measures phosphocreatine recovery time as an objective readout of mitochondrial capacity. Research-grade; note it does not track well with symptom severity.
Treatment options & their evidence
Graded honestly — including treatments that failed in good trials, which is worth knowing.
L-arginine + vitamin C
Mixed evidencepromise 3 · 1 RCTThe strongest dataset signal in the metabolic space — improved walk distance, grip, and endothelial function — but from a single-blind, single-centre study needing double-blind replication.
Caution: Caution with hypotension and nitrates.
Creatine monohydrate
Weak evidencepromise 1.06 · 3 RCTsSmall, inconsistent signals from several high-risk-of-bias trials; cheap and very safe, but no large confirmatory RCT.
Caution: Loading can cause GI upset and water-weight; caution in kidney disease.
CoQ10 / NAD+ precursors / oxaloacetate
Failed in trialspromise 0 · 4 RCTsThe rigorous trials of CoQ10, NR/NAD+, oxaloacetate, and AXA1125 all missed their primary endpoints. Biologically plausible, but unproven and non-trivial in cost.
Caution: Mostly opportunity-cost and expense; quality of OTC products varies.