Selected publication milestones, not an exhaustive history or discovery priority claim.
1999 — 1999 healthyvolunteerMRS establishes reversible, region-dependent braincreatine exposure. Original PMID10484486.
2002 — 2002 doubleblind mentalfatigue/NIRS experiment reports restricted functional benefit. Original PMID11985880.
2003 — 2003 vegetarian crossover reports marked workingmemory and reasoning gains. Original PMID14561278.
2006 — 2006 controlled sleep-loss challenge reports task-specific protection. Original PMID16416332.
2008 — 2008 comprehensive rested-youngadult trial reports null cognitive outcomes. Original PMID18579168.
2011 — 2011 female vegetarian/omnivore trial suggests a memoryinteraction. Original PMID21118604.
2013 — 2013 olderwomen24week factorialtrial finds no cognitivecreatine benefit. Original PMID24098469.
2015 — 2015 hypoxicchallenge pairs neuralcreatine increase withpreservedattention. Original PMID25632150.
2017 — 2017 age/diet/tissue experiment separatesmusclePCr increases frombrainPCr nulls. Original PMID28572496.
2023 — 2023 preregistered123-person trial narrows earlylargeeffects and fails the dietaryinteraction. Original PMID37968687.
2024 — 2024 highsingle-dose sleep-loss trial pairsMRS andcognitiveeffects without isolatingmediation. Original PMID38418482.
2026 — 2026 smallmultiformulationmenopause trial supplies a selectedpositive replicationlead. Original PMID40854087.
2026 — 2026 lowerdosesleep-loss crossover extendschallenge evidence withheterogeneouscorrectedoutcomes. Original PMID42075005.
The minimum cognitive effect that matters for everyday functioning has not been established by brief laboratory scores.
Preintervention absolute brain creatine, dietary pattern, sex and age need prospectively powered interaction tests; vegetarian status cannot substitute for low brain stores.
Dose and exposure comparisons should separate totalcreatine from PCr/ATP ratios and regional from wholebrain engagement.
The mediator remains unmanipulated in healthy-adult human trials; paired changes are not evidence of necessity.
Long-term dementia prevention or biological-age reversal is a separate clinical endpoint, not inferred from muscle gains, mouse longevity or single-arm AD tests.
A preregistered multicenter parallel oral-creatine/placebo trial in healthy adults, stratified before outcomes by sleep challenge versus rested condition, age, sex and diet, powered for a small effect and paired with absolute brain MRS; add a justified orthogonal mediator/dissociation component rather than calling correlation mediation.