Methylene Blue for Fatigue

Finding: Single low-dose oral MB significantly increased bilateral insular cortex activity during sustained attention (p=0.008-0.01) and increased prefrontal/parietal/occipital activation across encoding/maintenance/retrieval phases (p=0.0003-0.03), with ~7% improvement in correct short-term memory responses vs placebo (p<0.01). No cerebrovascular reactivity change. Sample size very small; single-dose acute design; no fatigue scale used.

Finding: Across pooled trials, MB-class compounds showed mixed cognitive results: Wischik 2008 phase 2 reported -6.8 ADAS-cog units vs -7.8 placebo at 60 mg TID. Two phase 3 LMTM trials (Gauthier 2016, Wilcock 2018) failed primary endpoints as add-on therapy; post-hoc 'monotherapy' subgroup suggested 4-16 mg/day benefit but was not pre-specified and TauRx-sponsored. No fatigue endpoint reported in any trial. Substantial industry sponsorship bias flagged.

Finding: Mechanistic plausibility for MB to mitigate mitochondrial-dysfunction-driven fatigue (ATP↑, ROS↓ at low doses 0.5-2 mg/kg; biphasic dose response with prooxidant effects >5 mg/kg). Evidence is exclusively preclinical (rodent ischemia/TBI, Parkinson's/AD cell models). Authors explicitly note absence of human chronic-supplementation RCTs.

Finding: MB improved muscle mitochondrial function markers and grip strength in aged mice; human translation data is exploratory and underpowered. No subjective fatigue scale reported. Cannot draw inference for human fatigue endpoints.