{
  "cutoff": "2026-10-12",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "10484486",
      "year": "1999",
      "title": "Increase of total creatine in human brain after oral supplementation of creatine-monohydrate.",
      "doi": "10.1152/ajpregu.1999.277.3.R698",
      "url": "https://pubmed.ncbi.nlm.nih.gov/10484486/",
      "interpretation": "1999 healthyvolunteerMRS establishes reversible, region-dependent braincreatine exposure."
    },
    {
      "pmid": "11985880",
      "year": "2002",
      "title": "Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.",
      "doi": "10.1016/s0168-0102(02)00007-x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/11985880/",
      "interpretation": "2002 doubleblind mentalfatigue/NIRS experiment reports restricted functional benefit."
    },
    {
      "pmid": "14561278",
      "year": "2003",
      "title": "Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.",
      "doi": "10.1098/rspb.2003.2492",
      "url": "https://pubmed.ncbi.nlm.nih.gov/14561278/",
      "interpretation": "2003 vegetarian crossover reports marked workingmemory and reasoning gains."
    },
    {
      "pmid": "16416332",
      "year": "2006",
      "title": "Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol.",
      "doi": "10.1007/s00213-005-0269-z",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16416332/",
      "interpretation": "2006 controlled sleep-loss challenge reports task-specific protection."
    },
    {
      "pmid": "18579168",
      "year": "2008",
      "title": "Creatine supplementation does not improve cognitive function in young adults.",
      "doi": "10.1016/j.physbeh.2008.05.009",
      "url": "https://pubmed.ncbi.nlm.nih.gov/18579168/",
      "interpretation": "2008 comprehensive rested-youngadult trial reports null cognitive outcomes."
    },
    {
      "pmid": "21118604",
      "year": "2011",
      "title": "The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.",
      "doi": "10.1017/S0007114510004733",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21118604/",
      "interpretation": "2011 female vegetarian/omnivore trial suggests a memoryinteraction."
    },
    {
      "pmid": "24098469",
      "year": "2013",
      "title": "Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: a randomized double-blind study.",
      "doi": "10.1371/journal.pone.0076301",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24098469/",
      "interpretation": "2013 olderwomen24week factorialtrial finds no cognitivecreatine benefit."
    },
    {
      "pmid": "25632150",
      "year": "2015",
      "title": "Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation.",
      "doi": "10.1523/JNEUROSCI.3113-14.2015",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25632150/",
      "interpretation": "2015 hypoxicchallenge pairs neuralcreatine increase withpreservedattention."
    },
    {
      "pmid": "28572496",
      "year": "2017",
      "title": "Effect of age, diet, and tissue type on PCr response to creatine supplementation.",
      "doi": "10.1152/japplphysiol.00248.2017",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28572496/",
      "interpretation": "2017 age/diet/tissue experiment separatesmusclePCr increases frombrainPCr nulls."
    },
    {
      "pmid": "37968687",
      "year": "2023",
      "title": "The effects of creatine supplementation on cognitive performance-a randomised controlled study.",
      "doi": "10.1186/s12916-023-03146-5",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37968687/",
      "interpretation": "2023 preregistered123-person trial narrows earlylargeeffects and fails the dietaryinteraction."
    },
    {
      "pmid": "38418482",
      "year": "2024",
      "title": "Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.",
      "doi": "10.1038/s41598-024-54249-9",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38418482/",
      "interpretation": "2024 highsingle-dose sleep-loss trial pairsMRS andcognitiveeffects without isolatingmediation."
    },
    {
      "pmid": "40854087",
      "year": "2026",
      "title": "The Effects of 8-Week Creatine Hydrochloride and Creatine Ethyl Ester Supplementation on Cognition, Clinical Outcomes, and Brain Creatine Levels in Perimenopausal and Menopausal Women (CONCRET-MENOPA): A Randomized Controlled Trial.",
      "doi": "10.1080/27697061.2025.2551184",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40854087/",
      "interpretation": "2026 smallmultiformulationmenopause trial supplies a selectedpositive replicationlead."
    },
    {
      "pmid": "42075005",
      "year": "2026",
      "title": "Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance.",
      "doi": "10.3390/nu18081192",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42075005/",
      "interpretation": "2026 lowerdosesleep-loss crossover extendschallenge evidence withheterogeneouscorrectedoutcomes."
    }
  ],
  "gaps": [
    "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."
  ],
  "decisive_experiment": "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."
}