In plain terms

The claim being assessed: Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.

Where the evidence stands: Ε — Causal in a specific setting. It genuinely causes the effect in one well-defined situation, but that does not extend to the wider claim.

What this mechanism does: This makes the process worse or keeps it going, but something else starts it.

Strongest evidence for it: The registered primary-subclaim rule selects SC2. Positive controlled cognitive effects in defined energetic-stress settings support Ε with Moderate confidence. Rested-adult and older-women nulls delimit generalization. Brain target engagement and muscle efficacy do not establish cognitive mediation, dementia prevention or routine enhancement across contexts. Weakest-link returns Γ; primary-subclaim and scope-matched return Ε.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means

Creatine can preserve selected cognitive performance under experimental energetic stress; evidence for routine enhancement in rested healthy adults is inconsistent, and the brain mediator remains unisolated.

Implications for health and treatment: The registered primary-subclaim rule selects SC2. Positive controlled cognitive effects in defined energetic-stress settings support Ε with Moderate confidence. Rested-adult and older-women nulls delimit generalization. Brain target engagement and muscle efficacy do not establish cognitive mediation, dementia prevention or routine enhancement across contexts. Weakest-link returns Γ; primary-subclaim and scope-matched return Ε.

Limits for individual care: 61 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness. The grade applies to the exact registered claim; stronger findings for narrower subclaims remain separate. No complete-paper audit or blinded calibration is claimed. This educational review does not establish an individual treatment recommendation.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

Source checking used bounded original primary abstract passages/status records and selected original partial-body passages. No complete-abstract or complete-paper audit, or independent scientific peer review, is claimed. Detailed access counts and limitations appear in the review.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 61 primary reports; claims: 66; verified: 66; unverified: 0. Verification is bounded attribution. Access: 5 partial-body and 56 bounded abstract/status examinations. Literature cutoff: 2026-10-12; source examination UTC date: 2026-10-13. No complete-paper audit or blinded calibration claimed.

Adversarial review: Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 4 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

Creatine can preserve selected cognitive performance under experimental energetic stress; evidence for routine enhancement in rested healthy adults is inconsistent, and the brain mediator remains unisolated.

Deciding 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.

Belief versus evidence: The registered primary-subclaim rule selects SC2. Positive controlled cognitive effects in defined energetic-stress settings support Ε with Moderate confidence. Rested-adult and older-women nulls delimit generalization. Brain target engagement and muscle efficacy do not establish cognitive mediation, dementia prevention or routine enhancement across contexts. Weakest-link returns Γ; primary-subclaim and scope-matched return Ε.

Best-supported rival: Baseline energetic demand modifies benefit. PMID37968687 directly tests vegetarian/omnivore moderation and preregistered rested-adult tasks: the dietary interaction is absent and effects are small/uncertain, narrowing broad enhancement toward context-dependent performance rather than disproving every positive challenge result.

COMPETING MECHANISTIC MODELS

Rank 1: Baseline energetic demand modifies benefit (Ε). Creatine has task-specific cognitive effects under experimentally measured energetic stress, with inconsistent benefits in ordinary rested conditions. Sleep-loss and hypoxia trials provide positive cognitive contrasts while comprehensive rested-adult and older-women trials provide relevant negative boundaries. Dietary and sex modifiers remain inconsistent; challenge studies are small and high doses cannot be generalized to everyday protocols.

Rank 2: Oral creatine improves cognitive performance (Ε). Oral creatine causes improvement in some tested cognitive outcomes in otherwise healthy adults. Controlled vegetarian, fatigue, sleep-loss and hypoxia studies retain genuine positive results. The large preregistered trial finds only small uncertain effects, several domains are null, and stable daily-function benefit is untested.

Rank 3: Target engagement without reliable cognitive gain (Γ). Brain creatine or energetic ratios can move without a measurable cognitive improvement; brain and muscle handling differ. MRS protocols show exposure-specific and sometimes null brain responses; young-adult dose trials find no cognition/fNIRS gain. Some paired stress-challenge studies show both engagement and performance, so this cannot explain every positive cognitive contrast.

Rank 4: Expectancy and practice account for apparent gain (Β). Repeated testing, imperfect blinding and participant expectations generate some apparent improvements. Trial order/practice effects, solubility differences, selected outcomes and uncontrolled pilot improvements supply credible confounders. No examined trial experimentally isolated expectancy as the sufficient cause; blinded positive contrasts prevent a blanket placebo-only verdict.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.

The nominal is the clinical sufficiency proposition represented by SC2. Mechanism, superiority, additional indication and safety subclaims are separately reported and do not gate the registered efficacy claim. The original topic family and this narrower gradeable restatement are retained; no response-based exclusions are allowed.

Selection: position 1 among the first five editorial traffic-priority families, registered on 2026-10-12. First five editorial traffic-priority families in health_topic_traffic_priority_2026-10-12/ranking.json; traffic proxies are not measured worldwide popularity or a preassigned verdict. Registered claim assessed against original sources; no independent blinded calibration is claimed.

Evidence and causal interpretation

Rubric fit: No shipped rubric directly covers non-hallucinogenic nutritional cognitive enhancement. Rubric07 supplies controlled cognitive intervention and mediation discipline; rubric06 supplies bioenergetic and biomarker-versus-function discipline. The explicit adaptation retains the canonical ladder and caps: a credible randomized supplement/placebo contrast with predefined cognitive tests is a clinical perturbation; acute hallucination-matched placebo and lifespan extension are not imposed on a nutritional cognitive-performance claim. Laboratory test performance is not automatically daily function, dementia prevention or healthy-aging benefit.

The examination includes 61 original reports across controlled cognitive experiments, brain exposure/measurement studies, explicit dietary and disease boundaries and transport/energetic animal mechanisms. This is not 61 healthy-adult cognitive efficacy trials. Source depth is full original abstracts or recorded selected passages, plus selected Methods/Results in five load-bearing papers; complete articles and supplements were not audited.

Rae 2003 PMID14561278 reports substantial working-memory and reasoning improvement in 45 vegetarian adults at 5 g/day for six weeks. That result remains positive, but vegetarian-only recruitment cannot test the diet-by-treatment interaction. Sandkuhler 2023 PMID37968687 uses a preregistered 123-person crossover, the same 5 g/day six-week exposure, with vegetarians and omnivores: small uncertain BDS effects, no clear Raven/exploratory benefit, no diet interaction and concrete solubility/practice concerns. The original Results explicitly distinguish evidence against the early large effect from weaker evidence about a small benefit.

Acute energetic challenges are the strongest mapped positive context: McMorris sleep-loss studies PMID16416332/17046034, Turner hypoxia PMID25632150 and Gordji-Nejad 2024/2026 PMID38418482/42075005 report selected performance preservation. They are small, specialized protocols; high acute exposure and forced sleep loss do not validate ordinary 3–5 g/day rested-adult enhancement. The 2026 paper uses a participant-level mixed model for longitudinal data but also pooled repeated-time contrasts and many subgroup endpoints; effect-size publicity should retain those analysis limits.

Contradictions define the boundary. PMID18579168 and 37759877 find no comprehensive rested young-adult cognitive improvement; PMID24098469 finds no 24-week cognitive benefit in older women with or without strength training. New 2026 menopause PMID40854087 and middle-age PMID42578920 positive selected outcomes warrant replication, with small multiformulation groups or explicitly exploratory endpoints retained. A benefit in one task is not an established general benefit in women, aging, intelligence or daily function.

Brain availability is real but variable: PMID10484486 demonstrates regionally dependent reversible increases after four weeks; PMID17185404 reports PCr/ATP changes largely due to reduced ATP, not a uniform ATP boost; PMID16377978 and 28572496 include short-protocol brain nulls despite muscle responses. PMID38418482 measures both cognitive and metabolic changes, while its 2025 hemispheric report PMID40520504 reuses the same study. Regional correlation does not isolate mediation.

Inherited transporter/GAMT biology, gene restoration, cyclocreatine rescue and intranasal rat delivery constrain the transport model, but their baseline defect, developmental timing, route and compound are outside otherwise healthy adult oral efficacy. The single-arm Alzheimer pilot PMID40395689 and biomarker reanalysis PMID41737290 share one 20-person trial and cannot establish prevention or a controlled treatment effect. Ordinary muscle-performance evidence cannot be transferred into this cognitive card.

Consensus was used as a browser-supported cross-check, not the source of grades or primary counts. Its fixed-dose description of the 2023 trial was imprecise, its vegetarian-brain-store inference was unmeasured, its menopause coverage omitted an asked-for original trial, and its gap grid was not a documented systematic census. Those specific points are corrected in evidence-bound reconciliation records.

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: primary-subclaim. The registered primary-subclaim rule selects SC2. Positive controlled cognitive effects in defined energetic-stress settings support Ε with Moderate confidence. Rested-adult and older-women nulls delimit generalization. Brain target engagement and muscle efficacy do not establish cognitive mediation, dementia prevention or routine enhancement across contexts. Weakest-link returns Γ; primary-subclaim and scope-matched return Ε. Sensitivities: weakest-link Γ; primary-subclaim Ε; scope-matched Ε.

Decisive-perturbation inventory and causal tally

[2] Preregistered 123-person crossover finds small uncertain working-memory effect no clear reasoning or exploratory-task benefit and no diet interaction Incomplete blinding assessment; order/practice effects; powered for larger effects not definitive exclusion of small benefit

[8] 29-person lower-dose sleep-loss crossover reports logical-task protection with heterogeneous corrected effects Repeated-time pooled tests and multiple subgroup endpoints; primary LMM accounts clustering but headline percentages not universal benefit

[9] 128 women double-blind trial reports vegetarian-specific memory gain and response-variability improvement Fluency/vigilance null; dietary group not randomized; absent measured brain baseline and interaction not reproduced in 2023

[11] 24-week older women factorial RCT finds no cognitive creatine effect with or without training Small per-arm sample; no brain exposure measure; exercise improves mood/strength without cognitive benefit

[12] Six-week 10/20 g randomized trial finds no cognitive-domain or PFC oxygenation effect 30 participants powered for large effect; fNIRS not brain creatine; uncertain small effects remain

[13] 15-person hypoxic crossover reports brain creatine increase and restored attention during oxygen deficit Severe acute hypoxia not ordinary rested cognition; mediator presumed not blocked; original body unavailable

[19] 15-person randomized sleep-loss crossover links acute high-dose creatine to metabolic changes and cognitive preservation Paired changes/correlations do not manipulate mediator; pooled timepoints and many voxel/endpoints; specialized high-dose challenge

[27] 45 vegetarian adults crossover reports large backward-digit and Raven gains with 5 g/day six weeks No brain exposure measurement; vegetarian-only recruitment cannot establish diet interaction; large effects not reproduced by 123-person trial

Tally: 5 positive qualifying study units across scoped subclaims; 18 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. 61 primary reports include explicit mechanism/boundary experiments; they are not 61 healthy-adult efficacy trials. GAA combinations, intranasal delivery, congenital/developmental rescue and AD pilots are not positive in-scope oral-creatine cognition crossings. Positive gene-expression and animal memory changes retain their biological context; no animal unit upgrades the primary healthy-adult claim. One same-participant metabolic reanalysis is not a new causal study.

Cap audit, precedence and Β/Γ/Δ boundary

A randomized cognitive contrast can cross the adapted human perturbation threshold for SC2 in its tested challenge context. A spectroscopy-only contrast remains a biomarker-limited leg, and correlations never establish SC4 mediation. Congenital transporter/synthesis, intranasal rat delivery and Alzheimer pilot evidence retain their distinct scope; no animal, familial or biomarker cap is silently generalized over the controlled adult cognitive set.

Universal six-cap audit: All six universal caps were considered: cell-only inference, unperturbed association, ectopic expression, biomarker-only intervention, forced transfer/seeding, and inherited-to-sporadic scope transfer. Each binds its offered inference; complementary same-scope causal classes are assessed together rather than re-capped in isolation.

Gamma hard-rule audit: Rubric07 functional-unblinding rule is not literally triggered by a non-hallucinogenic nutritional intervention; solubility, tolerability and allocation-guessing remain concrete risks. Mediation-by-correlation rule is triggered for SC4, where same-person spectroscopy/cognition associations are not manipulated mediators. Open-label and acute-pharmacodynamic rules bind the Alzheimer pilot and imaging-only components; they do not erase matched healthy-adult cognitive RCTs. The rubric06 single-species and biomarker-only rules bind animal-only and isolated energetic-marker inferences; they are not reapplied to replace the separately positive human cognitive contrasts.

SC1 cap: “Biomarker change without functional/phenotypic change caps at Γ.” Oral exposure changes regional brain creatine or energetic ratios in some dose/stress settings, with null brain responses elsewhere. This establishes target engagement. Paired cognitive improvement does not isolate the brain-marker contribution; the biomarker-only inference retains Γ, while the distinct clinical SC2 can reach Ε.

SC4 cap: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Paired brain spectroscopy and cognition, animal transport or synthesis perturbation, and neuronal assays make an energetic mechanism plausible. No examined healthy-adult study manipulated the proposed brain mediator while leaving oral supplementation intact. Regional correlation and congenital rescue do not establish supplementation-specific mediation; the mediation-by-correlation rule holds the human mediator proposition at Γ.

SC1 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. Oral exposure changes regional brain creatine or energetic ratios in some dose/stress settings, with null brain responses elsewhere. This establishes target engagement. Paired cognitive improvement does not isolate the brain-marker contribution; the biomarker-only inference retains Γ, while the distinct clinical SC2 can reach Ε.

SC2 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: yes. Positive controlled human cognitive contrasts exist in predefined sleep-loss, hypoxia and selected task/diet contexts. Larger preregistered rested-adult work finds small uncertain effects, with comprehensive young-adult and older-women null trials. This establishes context-specific causality at Ε rather than a universal brain enhancer. Repeated trials increase confidence but do not automatically constitute independent mechanistic lines. Nulls map the limit of full-context generalization rather than erasing the positive stress-context contrast; they are not counted twice as a second automatic downgrade.

SC3 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. Broad generalization across age, sex, diet and ordinary sleep conditions is not established. Vegetarian recruitment is not a randomized diet interaction; a larger trial directly failed to reproduce that interaction. Longer older-women and rested young-adult nulls challenge across-context claims. Residual transport/bioenergetic plausibility remains Γ; this is an evidential limitation of the positive universal proposition, not a claim that all subgroups fail.

SC4 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. Paired brain spectroscopy and cognition, animal transport or synthesis perturbation, and neuronal assays make an energetic mechanism plausible. No examined healthy-adult study manipulated the proposed brain mediator while leaving oral supplementation intact. Regional correlation and congenital rescue do not establish supplementation-specific mediation; the mediation-by-correlation rule holds the human mediator proposition at Γ.

SC1 applied rubric adaptation (distinct from the unchanged literal criterion): Applied criterion: controlled oral exposure changes quantified brain creatine/energetics in baseline-defined humans; paired challenge cognition supplies phenotype relevance but does not establish mediation. A spectroscopy-only leg retains the biomarker cap.

SC2 applied rubric adaptation (distinct from the unchanged literal criterion): Applied criterion: randomized/blinded non-hallucinogenic creatine versus matched placebo with cognitive outcomes, practice and carryover controls. Unlike psychedelic treatment, creatine has no unmistakable acute subjective effect requiring a psychoactive comparator; blinding checks still matter.

SC3 applied rubric adaptation (distinct from the unchanged literal criterion): Applied criterion: prespecified baseline-defined age/sex/diet/sleep interactions or adequately designed direct context contrasts, not responder-defined subgroups or significant-within-one-group comparisons.

SC4 applied rubric adaptation (distinct from the unchanged literal criterion): Applied criterion: mediator-specific human perturbation, dissociation or intervention on brain uptake/energy buffering with the supplement kept intact, while cognitive outcomes are measured. Correlation alone does not cross Δ.

SC1 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC2 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC3 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” triggered for healthy-adult supplementation mediator inference; correlations are not manipulations

SC4 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC4 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

Upward threshold ladder

SC1 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Replicate dose- and duration-dependent regional engagement with absolute creatine and phosphate measures, adequate sham/placebo, tissue corrections and paired cognition across rested and challenged adults.

SC2 Δ: “Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.” Satisfied: yes.

SC2 Ε: “Requires causal support restricted to a defined context — one diagnosis, one severity stratum, one treatment-resistant subgroup, or only with the accompanying psychotherapeutic scaffold.” Satisfied: yes.

SC2 Ζ: “Requires: - Independent multi-site replication by sponsor-independent teams, pre-registered, without outcome switching - Blinding-integrity reporting in each replicating trial - One result narrowing the mechanism against expectancy: mediator manipulation, blinded dose-response, or non-subjective congener” Satisfied: no. Run a preregistered multi-center parallel trial powered for a small clinically interpretable cognitive effect with practice-resistant alternate test forms and baseline-defined stress/diet strata; validate real-world function separately.

SC3 Δ: “Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.” Satisfied: no. Demonstrate replicated baseline-by-treatment interactions across age, sex, diet and sleep states with multiplicity control and measured preintervention brain creatine.

SC4 Δ: “Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.” Satisfied: no. Obtain a credible mediator dissociation or orthogonal manipulation showing that the cognitive supplement effect tracks specifically manipulated brain energy buffering rather than general fatigue, expectancy or peripheral performance.

Upper ladder: Dose contrasts, washout/crossover, genetic transport/synthesis and dietary population evidence were considered. Human positive cognition largely repeats one oral-intervention modality, genetic developmental deficiency is a different scope, and spectroscopy is not an independent efficacy line. No measured healthy-adult mediator manipulation, replicated predictive baseline rule or necessity-and-sufficiency dissociation carries the nominal beyond Ε.

Independence: These are complementary mechanistic checks with different failure modes, but they support different scopes. Positive cognitive RCT replication is one intervention line, and two modalities examining the same 15-person dataset remain one study. There is no valid pooling into Ζ for the complete healthy-adult cognitive claim.

Randomized oral adult cognitive perturbation [27, 19, 13]: Randomization reduces baseline diet/health selection; different tasks and laboratories improve confidence, but shared expectancy/practice/endpoint-selection can still affect this modality.

Direct cerebral exposure and tissue handling [60, 49, 55, 54]: Spectroscopy tests the assumption that oral exposure moves brain stores independently of self-reported benefit; it does not independently prove cognitive efficacy.

Transport/synthesis and delivery boundary [42, 31, 52, 28]: Genetic/route interventions test access and developmental energetic dependence, excluding oral uptake assumptions in those models; they do not establish supplementation benefit in otherwise healthy adults.

Falsification and pitfalls

Therapeutic effect misread as mechanistic proof. Paired cognitive/MRS changes do not show energetic mediation; congenital rescue does not establish healthy-adult enhancement.

Selective generalization. Sleep-loss, hypoxia, vegetarians, menopause, children and animals require antecedent-defined scopes.

Confirmation by biomarker. Regional creatine or phosphate ratios and fNIRS must not substitute for cognition or clinical function.

Causal-evidence tallies that do not survive an audit. Negative trials, duplicate analyses, GAA combinations, single-arm pilots and out-of-scope animal studies do not count as positive healthy-adult efficacy crossings.

Scope fitted to the result. No responder-defined narrowing or significant-within-subgroup rule is allowed.

Adversarial steelman: above, then below

Case for Ζ: multiple blinded trials in different laboratories and energetic challenges report cognitive benefits, MRS demonstrates exposure and genetic transporter/synthesis experiments make a compelling biological bridge. This is stronger than an anecdotal supplement claim and deserves credit for positive human contrasts.

Case for Δ: many positive studies are small, endpoints numerous, a large preregistered rested-adult study fails to reproduce early large effects and newer pooled repeated-time statistics need scrutiny. A single robust stress study could be the only defensible positive causal crossing.

Ζ is rejected because replication of one oral modality plus different-scope congenital/animal evidence does not meet the shared-failure independence test for healthy-adult cognition or isolate the mediator. Δ understates the repeatedly tested antecedent-defined stress/rest boundary; Ε retains restricted human causality while admitting inconsistent effect sizes and Moderate confidence.

Final score, causal direction and M/S/D

The registered primary-subclaim rule selects SC2. Positive controlled cognitive effects in defined energetic-stress settings support Ε with Moderate confidence. Rested-adult and older-women nulls delimit generalization. Brain target engagement and muscle efficacy do not establish cognitive mediation, dementia prevention or routine enhancement across contexts. Weakest-link returns Γ; primary-subclaim and scope-matched return Ε.

Oral supplementation precedes and sometimes attenuates experimentally induced cognitive decline, so step 2 epiphenomenon does not describe the intervention. Supplement-specific necessity, initiation and rate limitation are not established, and congenital deficiency cannot supply them in healthy adults. At step 5 the intervention is a reinforcing/stabilizing input to performance during energetic challenge, with the proposed brain mediator still separately Γ.

Momentum: Mechanistic only. The named artifact is recent published intervention output: the 2026 lower-dose sleep-deprivation trial PMID42075005 extending a controlled 2024 protocol, and the 2026 menopause and middle-age studies PMID40854087/42578920 adding baseline-defined populations. These are completed reports in new populations, not work addressing SC2's next threshold, which requires independent multi-site preregistered replication with blinding-integrity reporting plus one result narrowing the mechanism against expectancy; consistent with the Stability entry, no such study was identified as underway. This reflects actual intervention output, not publication counts; no verified named future trial is claimed.

Stability: Stable. No verified named pending result was identified that fixes the next threshold. A powered prespecified rested-versus-stress multi-center trial with mediator dissociation could raise or narrow the score, but this is a proposed experiment rather than a verified scheduled trigger.

Divergence: Contested. No single field-implied level is defensible from conflicting framings, so no implied level and no rung arithmetic are stated: supplement-market and some review framing imply a general cognitive enhancer, while the largest preregistered trial (PMID37968687) frames the same evidence as at most a small uncertain effect. No manufactured field consensus or arithmetic gap. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

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.

Readout: Prespecified cognitive composite and alternate-form domain tests at baseline and fixed follow-up, brain total creatine/PCr/ATP quantified separately, and independently validated daily function as a distinct endpoint. Controls: Identical appearance/solubility, measured allocation guesses and expectancy, blinded assessors, appropriate participant-level repeated-measures model, multiplicity control, adherence/diet measurement and no outcome-defined responder exclusions. Supporting: Replicated between-group cognitive improvement at the registered horizon with a baseline-defined interaction and a dissociation showing specific brain energetic mediation. Falsifying: Adequately precise null despite confirmed cerebral exposure, loss of effect after practice/expectancy control, or no cognitive dependency on an independently manipulated mediator.

KNOWLEDGE 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 total creatine from PCr/ATP ratios and regional from whole-brain 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.

REVIEWER NOTES

No literal shipped-rubric falsification pattern is applied as a second downgrade to the already mapped stress/rest context boundary. The large trial is not a multi-site central-rater failed replication, and creatine is not a drug with unmistakable acute subjective effects. Newer challenge analyses have statistical limitations rather than a verified retraction or falsification. Status notices remain attached. All scientific grading is open manual appraisal, not independent blind calibration or publication peer review. Coordinating appraisal retained the clinical Ε and restricted SC1 target-engagement inference to Γ. Actual source attribution was checked for the preregistered 123-person trial, sleep-loss phosphate study, older-women factorial null and young-adult dose null. No independent blinded regrade is claimed.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

Consensus and original-source reconciliation

Original Methods specifies one 5 g/day dose for six weeks per phase in a preregistered 123-person randomized crossover. Original Results distinguishes a small uncertain BDS effect from no clearRaven/exploratory benefit; it does not prove literally zero possible effect. Original PMID37968687.

Original 2023 Results directly tests the dietinteraction and finds no predicted difference; Rae 2003 vegetarian recruitment does not supply an omnivore contrast or measured brain deficiency. Lower muscle stores cannot be assumed to mean lowerbrainstores. Original PMID37968687.

OriginalMethods confirms a 15-person randomized high-dose sleep-loss crossover with spectroscopy/cognition and correlations. OriginalResults reports regionalcreatine/phosphate changes and performance shifts; no mediator perturbation occurs. Agreement on unproven mediation is retained, with multiple voxel/timepoint analysis limits stated. Original PMID38418482.

Original 2025 abstract identifies a new analysis of the previously published study. This is one 15-person dataset with PMID38418482, not independent replication or a second causal line. Original PMID40520504.

Original 2026 selectedMethods uses a 29-person crossover with participant-levelLMM plus pooled repeated-time contrasts. OriginalResults shows heterogeneous corrected outcomes and subgroup effects; a headline 12 percent or a single improved domain is not uniform reversal of impairment or a validated sex-specific dose rule. Original PMID42075005.

Original 2026 abstract reports 36 women randomized to three hydrochloride/ethylester formulations orplacebo and selected reactiontime/frontalcreatine gains. It is retained as a small recent positive with multiplecomparisons and unavailablebody, rather than erased by a provider coverage gap or accepted as broadmenopausecognition proof. Original PMID40854087.

OriginalMethods/Results confirm 56 healthy older women, codedcreatine/placebo with andwithouttraining, and no cognitive differences; training mood/strength benefit was not an additivecreatine cognitive effect. Original PMID24098469.

The examined 2023 trial pairs cognition withfNIRS, notMRS, and is null. Other records pairMRS/cognition inchildren andmenopause, while the 2023 adult trial has noMRS. This bounded set supports a need for wellpowered pairedstudies but cannot verify an absolute absence claim about every restedomnivoretrial; providergrid counts are not a systematic census. Original PMID37759877.

Originalabstract confirms the population/exposure/positive cognitive findings. Largeeffects remain a real result, but no samepersonbrainmeasurement establishes energeticmediation and subsequentlargertrial narrows expected magnitude. Original PMID14561278.

Consensus was used to identify literature and cross-check specific claims about design, endpoints, scope and research gaps. Those aspects were checked against original primary abstracts/status records and selected original Methods/Results passages. Consensus output was not treated as original full text. Provider search omissions are not evidence that a study does not exist. Source access and examination receipts are retained. Scite use or monthly unavailability is recorded per case; provider citation counts do not change causal grades.

Research timeline and gaps: Creatine and Cognitive Performance

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 older-women 24-week 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 preregistered 123-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 lower-dosesleep-loss crossover extendschallenge evidence withheterogeneouscorrectedoutcomes. Original PMID42075005.

Research 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 total creatine from PCr/ATP ratios and regional from whole-brain 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.

Boundary 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.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1. Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-14.

Scope of checks. Reference PMIDs verified against PubMed metadata: 61/61 resolve to the stated first author, title, journal and year. Retraction and expression-of-concern screen: none found. Load-bearing claims spot-checked against the primary records: 15, chosen as the ones the level depends on. Scoring logic re-derived against the framework reference and SKILL.md (hard caps, the pre-registered primary-subclaim rule, the mapped-boundary test that separates Delta from Epsilon, the shared-failure independence test for Zeta, and the M/S/D artifacts). Internal consistency checked between AT A GLANCE, the subclaim matrix, the final-score block and the score card.

Attribution audit. Every checked claim matched its source, including several that are easy to get wrong: Rae 2003's benefit in 45 vegetarian adults at 5 g/day for six weeks (PMID 14561278); the preregistered 123-person crossover finding the creatine effect bordering significance for backward digit span, null for Raven's matrices, and no vegetarian advantage (PMID 37968687); the two McMorris sleep-deprivation trials, in which benefit was confined to complex central-executive tasks (PMIDs 16416332, 17046034); the hypoxia trial restoring attentional capacity with a 9.2% rise in brain creatine (PMID 25632150); the comprehensive rested young-adult nulls (PMIDs 18579168, 37759877); the 56-woman, four-arm older-women factorial trial with no cognitive effect (PMID 24098469); the regionally dependent and reversible brain-creatine rise after four weeks (PMID 10484486); the finding that the PCr/ATP shift was driven largely by a fall in ATP rather than a uniform ATP boost (PMID 17185404); the 36-woman menopause formulation trial (PMID 40854087); the explicitly exploratory middle-age trial (PMID 42578920); and the single-arm 20-patient Alzheimer pilot whose bioenergetic and hemispheric reports reuse the same cohort (PMIDs 40395689, 41737290, 40520504). No citation inversion or population substitution was found.

Rejected findings (checked, no change).

1. The level. Both adjacent rungs were argued. Delta was rejected because the context boundary is mapped rather than untested: internal negative controls exist on both sides (rested young-adult and older-women nulls against sleep-loss and hypoxia positives), and the framework states that a mapped boundary means Epsilon while an untested one means Delta. Zeta was rejected because the positive human cognitive results are one oral-supplement modality, the spectroscopy work is target engagement rather than an efficacy line, and the congenital and animal transport evidence sits in a different scope; a single systematic error about expectancy, practice or endpoint selection in supplement trials could defeat the whole positive set. The level stands at Epsilon with Moderate confidence.
2. Aggregation. Primary-subclaim was pre-registered, SC2 is named, and both alternatives are reported (weakest-link Gamma, scope-matched Epsilon). SC2's declared scope matches the central claim's scope, so the scope-matched reading is not the "highest subclaim" misread. No change.
3. Citation years. Fourteen references print a year one later than the PubMed e-pub year. Rejected per the standing print-versus-e-pub convention.
4. Collective-author defect, empty DOI fields, retrieval handles, "PMID not supplied" strings. Screened for; none present.
5. Rubric routing. A nutritional cognitive-performance claim has no dedicated rubric; the review routes it through the psychiatry/neuromodulation and metabolism rubrics, declares the adaptation, and quotes the literal criteria unchanged. That is the framework's prescribed response to a rubric gap. No change.

Residual limitations. One correction in this pass (AR-4) came from a systematic artifact reported by the lead mid-pass and was applied after the first three; the renderer defect that prints the nominal as the best-supported rival was checked here and does not apply, because models_evaluated[0] is the rank-1 non-nominal model. The same builder defect also produced word-to-word fusions with no numeral to anchor them ("wellpowered", "lowerbrainstores", "restedomnivoretrial", "samepersonbrainmeasurement", "codedcreatine", "andwithouttraining"), mostly in the evidence cards, the reconciliation records and the timeline. Those cannot be repaired by exact string substitution without risking a change of meaning, and they are reported to the package builder rather than patched here; the document is therefore cleaner but not fully clean. The shipped validator is version 2.4 and enforces the v5.4 lay-summary requirement; this is a v5.3 package, so it returns one FAIL, the missing lay summary, both before and after this pass, and no lay summary was fabricated to clear it. Access depth is unchanged: 5 partial-body and 56 bounded abstract or status examinations.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-14.

REFERENCES

1. Korovljev D, Ostojic J, Panic J et al. 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. Journal of the American Nutrition Association. 2026. PMID 40854087. DOI: 10.1080/27697061.2025.2551184. Access: abstract_metadata. Study: PMID40854087.

2. Sandkühler JF, Kersting X, Faust A et al. The effects of creatine supplementation on cognitive performance-a randomised controlled study. BMC medicine. 2023. PMID 37968687. DOI: 10.1186/s12916-023-03146-5. Access: full_text_partial. Study: PMID37968687.

3. McMorris T, Mielcarz G, Harris RC et al. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition. 2007. PMID 17828627. DOI: 10.1080/13825580600788100. Access: abstract_metadata. Study: PMID17828627.

4. McMorris T, Harris RC, Swain J et al. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology. 2006. PMID 16416332. DOI: 10.1007/s00213-005-0269-z. Access: abstract_metadata. Study: PMID16416332.

5. McMorris T, Harris RC, Howard AN et al. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiology & behavior. 2007. PMID 17046034. DOI: 10.1016/j.physbeh.2006.08.024. Access: abstract_metadata. Study: PMID17046034.

6. Wu J, Qiu P, Li Y. Acute creatine supplementation enhances technical performance in adolescent basketball players under cognitive-motor dual-task condition. Journal of the International Society of Sports Nutrition. 2025. PMID 40758095. DOI: 10.1080/15502783.2025.2542369. Access: abstract_metadata. Study: PMID40758095.

7. Mabrey G, Koozehchian MS, Newton AT et al. The Effect of Creatine Nitrate and Caffeine Individually or Combined on Exercise Performance and Cognitive Function: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial. Nutrients. 2024. PMID 38542677. DOI: 10.3390/nu16060766. Access: abstract_metadata. Study: PMID38542677.

8. Gordji-Nejad A, Matusch A, Hengstler L et al. Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance. Nutrients. 2026. PMID 42075005. DOI: 10.3390/nu18081192. Access: full_text_partial. Study: PMID42075005.

9. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. The British journal of nutrition. 2011. PMID 21118604. DOI: 10.1017/S0007114510004733. Access: abstract_metadata. Study: PMID21118604.

10. Chun J, Liu Y, Kibler GL et al. Effects of creatine supplementation with and without exercise and diet intervention on body composition, cognitive function, and markers of health in middle-aged and older adults. Journal of the International Society of Sports Nutrition. 2026. PMID 42578920. DOI: 10.1080/15502783.2026.2716273. Access: abstract_metadata. Study: PMID42578920.

11. Alves CR, Merege Filho CA, Benatti FB et al. Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: a randomized double-blind study. PloS one. 2013. PMID 24098469. DOI: 10.1371/journal.pone.0076301. Access: full_text_partial. Study: PMID24098469.

12. Moriarty T, Bourbeau K, Dorman K et al. Dose-Response of Creatine Supplementation on Cognitive Function in Healthy Young Adults. Brain sciences. 2023. PMID 37759877. DOI: 10.3390/brainsci13091276. Access: full_text_partial. Study: PMID37759877.

13. Turner CE, Byblow WD, Gant N. Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2015. PMID 25632150. DOI: 10.1523/JNEUROSCI.3113-14.2015. Access: abstract_metadata. Study: PMID25632150.

14. Ben Maaoui K, Delleli S, Mahdi N et al. Effects of Creatine Monohydrate Loading on Sleep Metrics, Physical Performance, Cognitive Function, and Recovery in Physically Active Men: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. Nutrients. 2025. PMID 41470776. DOI: 10.3390/nu17243831. Access: abstract_metadata. Study: PMID41470776.

15. Fernandez-Garrido J, Martin EG, Saez-Berlanga A et al. Effects of high-load, velocity-intentional variable resistance training combined with creatine supplementation on neuroplasticity, oxidative stress, inflammation, physical function, cognitive performance and quality of life in older adults: A randomized, double-blind, placebo-controlled trial. Experimental gerontology. 2026. PMID 41941966. DOI: 10.1016/j.exger.2026.113122. Access: abstract_metadata. Study: PMID41941966.

16. VAN Cutsem J, Roelands B, Pluym B et al. Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills? Medicine and science in sports and exercise. 2020. PMID 31403610. DOI: 10.1249/MSS.0000000000002122. Access: abstract_metadata. Study: PMID31403610.

17. Rawson ES, Lieberman HR, Walsh TM et al. Creatine supplementation does not improve cognitive function in young adults. Physiology & behavior. 2008. PMID 18579168. DOI: 10.1016/j.physbeh.2008.05.009. Access: abstract_metadata. Study: PMID18579168.

18. Chun J, Babakhani K, Gonzalez DE et al. Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults. Journal of the International Society of Sports Nutrition. 2026. PMID 42730704. DOI: 10.1080/15502783.2026.2711032. Access: abstract_metadata. Study: PMID42730704.

19. Gordji-Nejad A, Matusch A, Kleedörfer S et al. Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation. Scientific reports. 2024. PMID 38418482. DOI: 10.1038/s41598-024-54249-9. Access: full_text_partial. Study: GordjiNejad_highdose_sleep2024.

20. Dworak M, Kim T, Mccarley RW et al. Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats. Journal of sleep research. 2017. PMID 28397310. DOI: 10.1111/jsr.12523. Access: abstract_metadata. Study: PMID28397310.

21. Gordji-Nejad A, Matusch A, Kleedörfer S et al. Hemispheric asymmetry in high-energy phosphate consumption during sleep-deprivation is balanced by creatine. Frontiers in neuroscience. 2025. PMID 40520504. DOI: 10.3389/fnins.2025.1515761. Access: abstract_metadata. Study: GordjiNejad_highdose_sleep2024.

22. Ostojic SM. Guanidinoacetic acid loading for improved location-specific brain creatine. Clinical nutrition (Edinburgh, Scotland). 2021. PMID 32439266. DOI: 10.1016/j.clnu.2020.05.003. Access: abstract_metadata. Study: GAA_loading_participant_overlap_unresolved.

23. Ostojic SM, Ostojic J. Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study. Neuroscience letters. 2026. PMID 42061673. DOI: 10.1016/j.neulet.2026.138616. Access: abstract_metadata. Study: PMID42061673.

24. Burridge J, Boolani A, Zhang Z et al. Real-world creatine supplementation: a large-scale cross-sectional study of use, knowledge, and experiences. Journal of the International Society of Sports Nutrition. 2026. PMID 42479961. DOI: 10.1080/15502783.2026.2702952. Access: abstract_metadata. Study: PMID42479961.

25. Ostojic SM, Korovljev D, Stajer V. Dietary creatine and cognitive function in U.S. adults aged 60 years and over. Aging clinical and experimental research. 2021. PMID 33866527. DOI: 10.1007/s40520-021-01857-4. Access: abstract_metadata. Study: PMID33866527.

26. Smith AN, Choi IY, Lee P et al. Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition. Alzheimer's & dementia (New York, N. Y.). 2025. PMID 40395689. DOI: 10.1002/trc2.70101. Access: abstract_metadata. Study: NCT05383833_ADpilot.

27. Rae C, Digney AL, McEwan SR et al. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proceedings. Biological sciences. 2003. PMID 14561278. DOI: 10.1098/rspb.2003.2492. Access: abstract_metadata. Study: PMID14561278.

28. Chen K, Hu X. Intranasal creatine administration increases brain creatine level and improves Barnes maze performance in rats. Brain research bulletin. 2023. PMID 37429386. DOI: 10.1016/j.brainresbull.2023.110703. Access: abstract_metadata. Study: PMID37429386.

29. Flögel S, Strater M, Fischer D et al. A creatine efflux transporter in oligodendrocytes. The FEBS journal. 2025. PMID 39792585. DOI: 10.1111/febs.17382. Access: abstract_metadata. Study: PMID39792585.

30. Li S, Bianconi S, van der Veen JW et al. Oxidative phosphorylation in creatine transporter deficiency. NMR in biomedicine. 2021. PMID 32990357. DOI: 10.1002/nbm.4419. Access: abstract_metadata. Study: PMID32990357.

31. Montani C, Iovino L, Di Vetta F et al. Connectomic and behavioural alterations in creatine transporter deficiency are partially normalized by gene therapy. Brain : a journal of neurology. 2026. PMID 40729420. DOI: 10.1093/brain/awaf275. Access: abstract_metadata. Study: PMID40729420.

32. Wang K, Huang J, Ju L et al. Creatine mapping of the brain at 3T by CEST MRI. Magnetic resonance in medicine. 2024. PMID 37814487. DOI: 10.1002/mrm.29876. Access: abstract_metadata. Study: PMID37814487.

33. Wawro AM, Gajera CR, Baker SA et al. Creatine transport and pathological changes in creatine transporter deficient mice. Journal of inherited metabolic disease. 2021. PMID 33389772. DOI: 10.1002/jimd.12358. Access: abstract_metadata. Study: PMID33389772.

34. Chen HR, Zhang-Brotzge X, Morozov YM et al. Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis. JCI insight. 2021. PMID 34324436. DOI: 10.1172/jci.insight.140173. Access: abstract_metadata. Study: PMID34324436.

35. Ling J, Kritikos M, Tiplady B. Cognitive effects of creatine ethyl ester supplementation. Behavioural pharmacology. 2009. PMID 19773644. DOI: 10.1097/FBP.0b013e3283323c2a. Access: abstract_metadata. Study: PMID19773644.

36. Bahari Z, Jangravi Z, Hatef B et al. Creatine supplementation protects spatial memory and long-term potentiation against chronic restraint stress. Behavioural pharmacology. 2023. PMID 37462147. DOI: 10.1097/FBP.0000000000000739. Access: abstract_metadata. Study: PMID37462147.

37. Oliveira EF, Forbes SC, Borges EQ et al. Association between dietary creatine and visuospatial short-term memory in older adults. Nutrition and health. 2023. PMID 35603861. DOI: 10.1177/02601060221102273. Access: abstract_metadata. Study: PMID35603861.

38. Cunha MP, Lieberknecht V, Ramos-Hryb AB et al. Creatine affords protection against glutamate-induced nitrosative and oxidative stress. Neurochemistry international. 2016. PMID 26804444. DOI: 10.1016/j.neuint.2016.01.002. Access: abstract_metadata. Study: PMID26804444.

39. Sartini S, Lattanzi D, Di Palma M et al. Maternal Creatine Supplementation Positively Affects Male Rat Hippocampal Synaptic Plasticity in Adult Offspring. Nutrients. 2019. PMID 31461895. DOI: 10.3390/nu11092014. Access: abstract_metadata. Study: PMID31461895.

40. Adriano E, Garbati P, Salis A et al. Creatine salts provide neuroprotection even after partial impairment of the creatine transporter. Neuroscience. 2017. PMID 26930002. DOI: 10.1016/j.neuroscience.2016.02.038. Access: abstract_metadata. Study: PMID26930002.

41. Bender A, Beckers J, Schneider I et al. Creatine improves health and survival of mice. Neurobiology of aging. 2008. PMID 17416441. DOI: 10.1016/j.neurobiolaging.2007.03.001. Access: abstract_metadata. Study: PMID17416441.

42. Kurosawa Y, Degrauw TJ, Lindquist DM et al. Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. The Journal of clinical investigation. 2012. PMID 22751104. DOI: 10.1172/JCI59373. Access: abstract_metadata. Study: PMID22751104.

43. Ostojic SM, Ostojic J, Drid P et al. Dietary guanidinoacetic acid increases brain creatine levels in healthy men. Nutrition (Burbank, Los Angeles County, Calif.). 2017. PMID 27497517. DOI: 10.1016/j.nut.2016.06.001. Access: abstract_metadata. Study: GAA_loading_participant_overlap_unresolved.

44. Brustovetsky N, Brustovetsky T, Dubinsky JM. On the mechanisms of neuroprotection by creatine and phosphocreatine. Journal of neurochemistry. 2001. PMID 11208905. DOI: 10.1046/j.1471-4159.2001.00052.x. Access: abstract_metadata. Study: PMID11208905.

45. Zanini D, Todorovic N, Ostojic SM. Creatine with guanidinoacetic acid improves prefrontal brain oxygenation before, during, and after a cognitive task: A randomized controlled pilot trial. Nutrition and health. 2025. PMID 39569437. DOI: 10.1177/02601060241300236. Access: abstract_metadata. Study: PMID39569437.

46. Wideman C, Iemma A, Janolo O et al. Effect of Creatine Monohydrate on Spatial Working Memory, Body Weight, and Food Intake in Male and Female Rats. Nutrients. 2025. PMID 40647322. DOI: 10.3390/nu17132218. Access: abstract_metadata. Study: PMID40647322.

47. Almeida LS, Salomons GS, Hogenboom F et al. Exocytotic release of creatine in rat brain. Synapse (New York, N.Y.). 2006. PMID 16715490. DOI: 10.1002/syn.20280. Access: abstract_metadata. Study: PMID16715490.

48. Hautman ER, Kokenge AN, Udobi KC et al. Female mice heterozygous for creatine transporter deficiency show moderate cognitive deficits. Journal of inherited metabolic disease. 2014. PMID 23716276. DOI: 10.1007/s10545-013-9619-x. Access: abstract_metadata. Study: PMID23716276.

49. Pan JW, Takahashi K. Cerebral energetic effects of creatine supplementation in humans. American journal of physiology. Regulatory, integrative and comparative physiology. 2007. PMID 17185404. DOI: 10.1152/ajpregu.00717.2006. Access: abstract_metadata. Study: PMID17185404.

50. Sora I, Richman J, Santoro G et al. The cloning and expression of a human creatine transporter. Biochemical and biophysical research communications. 1994. PMID 7945388. DOI: 10.1006/bbrc.1994.2475. Access: abstract_metadata. Study: PMID7945388.

51. K Taylor M, Smith AN, Choi IY et al. Bioenergetic data from a creatine monohydrate pilot trial in Alzheimer's disease. Alzheimer's & dementia (New York, N. Y.). 2026. PMID 41737290. DOI: 10.1002/trc2.70228. Access: abstract_metadata. Study: NCT05383833_ADpilot.

52. Rosko LM, Gentile T, Smith VN et al. Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023. PMID 36732069. DOI: 10.1523/JNEUROSCI.2120-21.2022. Access: abstract_metadata. Study: PMID36732069.

53. Merege-Filho CA, Otaduy MC, de Sá-Pinto AL et al. Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2017. PMID 28079396. DOI: 10.1139/apnm-2016-0406. Access: abstract_metadata. Study: PMID28079396.

54. Wilkinson ID, Mitchel N, Breivik S et al. Effects of creatine supplementation on cerebral white matter in competitive sportsmen. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine. 2006. PMID 16377978. DOI: 10.1097/01.jsm.0000176372.67398.c8. Access: abstract_metadata. Study: PMID16377978.

55. Solis MY, Artioli GG, Otaduy MCG et al. Effect of age, diet, and tissue type on PCr response to creatine supplementation. Journal of applied physiology (Bethesda, Md. : 1985). 2017. PMID 28572496. DOI: 10.1152/japplphysiol.00248.2017. Access: abstract_metadata. Study: PMID28572496.

56. Michaelis T, Wick M, Fujimori H et al. Proton MRS of oral creatine supplementation in rats. Cerebral metabolite concentrations and ischemic challenge. NMR in biomedicine. 1999. PMID 10484820. DOI: 10.1002/(sici)1099-1492(199908)12:5<309::aid-nbm572>3.0.co;2-y. Access: abstract_metadata. Study: PMID10484820.

57. Stockler-Ipsiroglu S, van Karnebeek C, Longo N et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Molecular genetics and metabolism. 2014. PMID 24268530. DOI: 10.1016/j.ymgme.2013.10.018. Access: abstract_metadata. Study: PMID24268530.

58. Alessandrì MG, Bosetti C, Scaffei E et al. Advancing clinical insight into creatine transporter deficiency: long term outcome and new observations from the Italian cohort. Orphanet journal of rare diseases. 2026. PMID 41776642. DOI: 10.1186/s13023-026-04289-3. Access: abstract_metadata. Study: PMID41776642.

59. Nänto-Salonen K, Komu M, Lundbom N et al. Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology. 1999. PMID 10430418. DOI: 10.1212/wnl.53.2.303. Access: abstract_metadata. Study: PMID10430418.

60. Dechent P, Pouwels PJ, Wilken B et al. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. The American journal of physiology. 1999. PMID 10484486. DOI: 10.1152/ajpregu.1999.277.3.R698. Access: abstract_metadata. Study: PMID10484486.

61. Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neuroscience research. 2002. PMID 11985880. DOI: 10.1016/s0168-0102(02)00007-x. Access: abstract_metadata. Study: PMID11985880.

Source-specific evidence cards

[1] 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.

Shows: Small four-arm double-blind menopause trial reports reaction-time and frontal creatine gains at medium hydrochloride dose

Does not show: 36 participants multiple formulations endpoints; original body unavailable; regional engagement is not mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

[2] The effects of creatine supplementation on cognitive performance-a randomised controlled study.

Shows: Preregistered 123-person crossover finds small uncertain working-memory effect no clear reasoning or exploratory-task benefit and no diet interaction

Does not show: Incomplete blinding assessment; order/practice effects; powered for larger effects not definitive exclusion of small benefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph3, 1:Methods:paragraph4, 1:Methods:paragraph5, 1:Methods:paragraph20, 1:Methods:paragraph25, 2:Results:paragraph6, 2:Results:paragraph10, 2:Results:paragraph11, 2:Results:paragraph14, 2:Results:paragraph20, 2:Results:paragraph22, 2:Results:paragraph29. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[3] Creatine supplementation and cognitive performance in elderly individuals.

Shows: Short elderly controlled loading trial reports several memory-task gains

Does not show: 32 participants short duration placebo-first sequence and multiple outcomes; no brain mediator

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[4] Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol.

Shows: Double-blind controlled 19-person sleep-loss challenge shows task-specific protection after 24 hours

Does not show: Sleep loss plus exercise bundled; small sample multiple endpoints; no direct brain exposure measurement

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[5] Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior.

Shows: Creatine improves complex central executive task at 36 hours sleep loss with most other outcomes unchanged

Does not show: Restricted acute challenge; small trial; no general rested-adult inference

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[6] Acute creatine supplementation enhances technical performance in adolescent basketball players under cognitive-motor dual-task condition.

Shows: Adolescent athletic crossover improves some dual-task skill metrics and subtraction accuracy only during shooting

Does not show: Children outside registered adult scope; muscle and technical-skill components cannot isolate cognitive enhancement

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[7] The Effect of Creatine Nitrate and Caffeine Individually or Combined on Exercise Performance and Cognitive Function: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.

Shows: Creatine-nitrate plus caffeine improves Stroop interference in 12 trained men

Does not show: Combined formulation caffeine and nitrate prevent monohydrate-specific attribution; short exposure and small cohort

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[8] Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance.

Shows: 29-person lower-dose sleep-loss crossover reports logical-task protection with heterogeneous corrected effects

Does not show: Repeated-time pooled tests and multiple subgroup endpoints; primary LMM accounts clustering but headline percentages not universal benefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:2. Materials and Methods:paragraph1, 1:2. Materials and Methods:paragraph9, 1:2. Materials and Methods:paragraph10, 2:3. Results:paragraph8, 2:3. Results:paragraph9. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[9] The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.

Shows: 128 women double-blind trial reports vegetarian-specific memory gain and response-variability improvement

Does not show: Fluency/vigilance null; dietary group not randomized; absent measured brain baseline and interaction not reproduced in 2023

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[10] Effects of creatine supplementation with and without exercise and diet intervention on body composition, cognitive function, and markers of health in middle-aged and older adults.

Shows: 12-week randomized creatine component reports selected exploratory cognition and memory improvements in middle-aged adults

Does not show: Exercise/diet participation self-selected; many cognitive endpoints explicitly exploratory;64 completers

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[11] Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: a randomized double-blind study.

Shows: 24-week older women factorial RCT finds no cognitive creatine effect with or without training

Does not show: Small per-arm sample; no brain exposure measure; exercise improves mood/strength without cognitive benefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Material and Methods:paragraph1, 1:Material and Methods:paragraph2, 1:Material and Methods:paragraph3, 1:Material and Methods:paragraph5, 1:Material and Methods:paragraph9, 2:Results:paragraph3, 2:Results:paragraph7, 2:Results:paragraph9. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[12] Dose-Response of Creatine Supplementation on Cognitive Function in Healthy Young Adults.

Shows: Six-week 10/20 g randomized trial finds no cognitive-domain or PFC oxygenation effect

Does not show: 30 participants powered for large effect; fNIRS not brain creatine; uncertain small effects remain

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:2. Materials and Methods:paragraph0, 1:2. Materials and Methods:paragraph5, 1:2. Materials and Methods:paragraph8, 2:3. Results:paragraph0, 2:3. Results:paragraph1. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[13] Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation.

Shows: 15-person hypoxic crossover reports brain creatine increase and restored attention during oxygen deficit

Does not show: Severe acute hypoxia not ordinary rested cognition; mediator presumed not blocked; original body unavailable

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

[14] Effects of Creatine Monohydrate Loading on Sleep Metrics, Physical Performance, Cognitive Function, and Recovery in Physically Active Men: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Shows: 14 active men crossover reports better digit-cancellation performance and subjective sleep

Does not show: Objective sleep and many recovery measures unchanged; task multiplicity short loading and exercise context

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[15] Effects of high-load, velocity-intentional variable resistance training combined with creatine supplementation on neuroplasticity, oxidative stress, inflammation, physical function, cognitive performance and quality of life in older adults: A randomized, double-blind, placebo-controlled trial.

Shows: Older-adult sixarm trial reports training effects and creatine additions mainly on strength/function and biomarkers

Does not show: Abstract does not establish an isolated creatine cognitive contrast; exercise gains cannot be credited to supplement

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[16] Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills?

Shows: 14-person mental-fatigue crossover improves prolonged Stroop accuracy but fails to prevent short visuomotor/Flanker decline

Does not show: Task-specific gains and physical-strength effects; no mediator measurement

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[17] Creatine supplementation does not improve cognitive function in young adults.

Shows: 22-person sixweek placebo trial finds no benefit across comprehensive youngadult neurocognitive tests

Does not show: Small cohort modest dose; null does not exclude all doses/domains or stress contexts

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[18] Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults.

Shows: GAA with or without creatine trial finds selected retrieval-speed changes and numerous null cognitive domains

Does not show: No creatine-only arm; many outcomes and near-significance findings; precursor attribution differs

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[19] Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.

Shows: 15-person randomized sleep-loss crossover links acute high-dose creatine to metabolic changes and cognitive preservation

Does not show: Paired changes/correlations do not manipulate mediator; pooled timepoints and many voxel/endpoints; specialized high-dose challenge

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph1, 1:Materials and methods:paragraph3, 1:Materials and methods:paragraph19, 1:Materials and methods:paragraph21, 2:Results:paragraph18, 2:Results:paragraph20, 2:Results:paragraph22, 2:Results:paragraph24, 2:Results:paragraph25, 2:Results:paragraph27. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

[20] Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats.

Shows: Rat oral supplementation alters sleep pressure adenosine and brain energetic measurements

Does not show: No human cognition; ATP decreases and PCr trend prevent simple moreATP account

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[21] Hemispheric asymmetry in high-energy phosphate consumption during sleep-deprivation is balanced by creatine.

Shows: Reanalysis of 2024 sleep-loss dataset reports creatine effects on hemispheric phosphate asymmetry

Does not show: Same 15 participants as PMID38418482 not independent trial; metabolite ratios not cognitive mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[22] Guanidinoacetic acid loading for improved location-specific brain creatine.

Shows: Secondary GAA-loading analysis reports location-dependent brain creatine increases and thalamic decrease

Does not show: Precursor not oral creatine; responder categorization postoutcome cannot define registered beneficiary scope; pooled source trials

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[23] Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.

Shows: Exploratory 12-woman MRS study correlates regional brain creatine with concentration complaints and estradiol

Does not show: No supplementation randomization; reference-age comparison and multiple correlations; no causal menopause mechanism

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[24] Real-world creatine supplementation: a large-scale cross-sectional study of use, knowledge, and experiences.

Shows: Supplement-user survey records strong loyalty but frequent unmet cognitive expectations and sex differences

Does not show: Selfselected app respondents selfreported exposure/outcomes no untreated comparator; cannot estimate efficacy or causal adverse-event incidence

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[25] Dietary creatine and cognitive function in U.S. adults aged 60 years and over.

Shows: NHANES older-adult dietary creatine estimate correlates weakly with digit-symbol scores

Does not show: Food pattern recall education and health confounding; not supplemental-creatine intervention

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[26] Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition.

Shows: 20-person uncontrolled Alzheimer pilot reports 11 percent brain creatine increase and improved repeated tests

Does not show: Disease outside healthy scope; singlearm practice/regression effects; not efficacy or mediation proof

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[27] Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.

Shows: 45 vegetarian adults crossover reports large backward-digit and Raven gains with 5 g/day six weeks

Does not show: No brain exposure measurement; vegetarian-only recruitment cannot establish diet interaction; large effects not reproduced by 123-person trial

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[28] Intranasal creatine administration increases brain creatine level and improves Barnes maze performance in rats.

Shows: Rat intranasal route increases regional brain creatine and Barnes performance more than oral route

Does not show: Intranasal research delivery is not oral human supplement; behavioral/exposure concurrence not isolated energy mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[29] A creatine efflux transporter in oligodendrocytes.

Shows: Heterologous transporter assays identify conditional SLC22A15 creatine efflux with oligodendrocyte expression

Does not show: Expression and cell efflux do not establish healthy-adult oral brain uptake or cognitive mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[30] Oxidative phosphorylation in creatine transporter deficiency.

Shows: Transporter-deficiency phosphorusMRS shows low PCr/creatine despite preserved oxidative-energy indices

Does not show: Congenital disease not healthy enhancement; developmental compensation; low creatine not simple globalATP failure

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[31] Connectomic and behavioural alterations in creatine transporter deficiency are partially normalized by gene therapy.

Shows: Perinatal gene restoration in transporterKO partly rescues networks and memory but leaves deficits and harms wildtype cognition

Does not show: Developmental ectopic gene therapy; not oralcreatine healthy-adult necessity/sufficiency; incomplete rescue

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[32] Creatine mapping of the brain at 3T by CEST MRI.

Shows: GAMT knockout and wildtype comparisons establish creatine and pH contributions to CEST signal

Does not show: Readout calibration only; CEST contains proteinarginine contribution and is not a pure cognitive mediator

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[33] Creatine transport and pathological changes in creatine transporter deficient mice.

Shows: TransporterKO study measures organ-specific labeled creatine uptake and pathology

Does not show: Severe congenital model and peripheral disease do not identify normaladult cognitive supplement response

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[34] Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis.

Shows: Transporter loss worsens energetic stress adaptation and intranasalcreatine partially rescues injury

Does not show: Genotype neonatalinjury and intranasal route differ from oral healthyadult cognitive augmentation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[35] Cognitive effects of creatine ethyl ester supplementation.

Shows: Double-blind creatineethylester study reports improvements on several cognitive measures

Does not show: Different chemicalform and objective adherence lacking; original abstract lacks detailed sample/effect sizes

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[36] Creatine supplementation protects spatial memory and long-term potentiation against chronic restraint stress.

Shows: Controlled adult rat stress study finds oralcreatine preservation of memory LTP and arborization

Does not show: High 2 g/kg animaldose; stress model not normalhuman scope; mechanism explicitly unresolved

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[37] Association between dietary creatine and visuospatial short-term memory in older adults.

Shows: 42 olderadults dietary intake correlates with Corsi and memory scores

Does not show: Small nonrandomized dietary study median splits nutritional confounding; no causal supplement contrast

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[38] Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

Shows: Neuronal cell and pretreated hippocampalslice studies show protection against toxic oxidative/glutamate insults

Does not show: Millimolar culture exposure injury endpoints and scavenging not healthyhuman cognitive mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[39] Maternal Creatine Supplementation Positively Affects Male Rat Hippocampal Synaptic Plasticity in Adult Offspring.

Shows: Maternalcreatine exposure produces lasting adult offspring excitability/LTP changes

Does not show: Developmental intervention and electrophysiological proxy no direct human cognitive endpoint

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[40] Creatine salts provide neuroprotection even after partial impairment of the creatine transporter.

Shows: Creatine salts differ in uptake and anoxic synaptic protection after transporter impairment

Does not show: Modifiedsalts transportblock anoxia not oralmonohydrate normaladult benefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[41] Creatine improves health and survival of mice.

Shows: Agedmouse oralcreatine study reports healthy-lifespan and neurobehavioral improvement

Does not show: Onebackground aging neurobehavioral outcomes do not demonstrate human longevity or dementia prevention

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[42] Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

Shows: TransporterKO mice respond to cyclocreatine with cognitive rescue while creatine fails

Does not show: Differentanalog congenital defect; supports transport boundary not ordinaryoralcreatine enhancement

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[43] Dietary guanidinoacetic acid increases brain creatine levels in healthy men.

Shows: Five men GAA series shows regional braincreatine gains but thalamic pattern differs

Does not show: Uncontrolled precursor dosing not oralcreatine cognition; possible overlap with secondaryGAA analyses

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[44] On the mechanisms of neuroprotection by creatine and phosphocreatine.

Shows: Creatine/PCr neuronalprotection experiments narrow secondaryglutamate but do not show dietary suppression of mitochondrial permeability transition

Does not show: Culturedinjury and isolatedmitochondria not cognitive mediator; proposed mitochondrial explanation has internal negativecontrol

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[45] Creatine with guanidinoacetic acid improves prefrontal brain oxygenation before, during, and after a cognitive task: A randomized controlled pilot trial.

Shows: 19-person randomized creatineGAA combination changes prefrontaloxygenation atrest/recovery

Does not show: Combinedprecursor attribution and oxygenbiomarker not measured cognitive benefit or creatine mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[46] Effect of Creatine Monohydrate on Spatial Working Memory, Body Weight, and Food Intake in Male and Female Rats.

Shows: Male/female rat watermaze trial finds practice-related workingmemory improvement independentofcreatine

Does not show: Animaltask and smallgroups; negativecontrol for automatic memoryenhancement not definitive human null

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[47] Exocytotic release of creatine in rat brain.

Shows: Ratbrain slices show electricallyevoked calcium/TTX-sensitive creatinerelease

Does not show: Neuromodulator plausibility not demonstrated contributionto supplement-associatedhumancognition

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[48] Female mice heterozygous for creatine transporter deficiency show moderate cognitive deficits.

Shows: Female transporterheterozygote mice have selective memorydeficits with otherdomains spared

Does not show: Congenital Xlinkedmosaic context no supplementcontrast; not universal necessity in healthyadults

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[49] Cerebral energetic effects of creatine supplementation in humans.

Shows: Seven-day humanMRS protocol altersbraincreatine and PCr/ATP ratio largelythroughdecreasedATP

Does not show: Energeticratio change not uniformlyincreasedATP or cognitivephenotype; no mediationmanipulation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[50] The cloning and expression of a human creatine transporter.

Shows: Clonedhumansodiumdependent transporter demonstrates creatineuptake and analoguecompetition

Does not show: Heterologouscelluptake doesnot prove brainoralexposure or healthycognitivebenefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[51] Bioenergetic data from a creatine monohydrate pilot trial in Alzheimer's disease.

Shows: SecondaryAlzheimerpilot reports peripheral energychanges but brainNAA/GSH remainunchanged

Does not show: Same NCT05383833 cohort as PMID40395689; uncontrolled and outofhealthyscope; peripheralmovement notbrainmediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[52] Cerebral Creatine Deficiency Affects the Timing of Oligodendrocyte Myelination.

Shows: Conditional/endogenous GAMTdeletion delaysoligodendrocytematuration with remyelination benefitfromcreatineanalogues

Does not show: Developmental/remyelination contexts not healthyadult cognition; distinct cellularroles beyondsimpleATP boost

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[53] Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study.

Shows: Healthychildren randomizedsupplementation shows neither regionalbraincreatine nor cognitiveimprovement

Does not show: Childrenoutsideadultscope; selectedMRSsubsample; short 7-day protocol

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

[54] Effects of creatine supplementation on cerebral white matter in competitive sportsmen.

Shows: Athlete placeboMRScomparison findsno deepfrontalwhitemattercreatinemovement after 5-day loading

Does not show: Small 18-person regionalstudy shortprotocol; no cognitiveendpoint

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[55] Effect of age, diet, and tissue type on PCr response to creatine supplementation.

Shows: Age/diet/tissue study finds musclePCr rise butno brainPCr response inalltestedgroups

Does not show: Singleblind placebo-first design andPCr not totaltissuecreatine; no cognitiveoutcomes; tissue-specificbaselineeffects

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[56] Proton MRS of oral creatine supplementation in rats. Cerebral metabolite concentrations and ischemic challenge.

Shows: Rat oralMRSstudy reports modestbraincreatine/metabolismchanges withoutchangedischemiclactatecourse

Does not show: Species andhigh-dose; metabolicphenotype notfunctional cognitivebenefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[57] Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.

Shows: GAMT48-patient cohort finds cerebralcreatine restorationand betterearlytreateddevelopmentaloutcomes

Does not show: Combinedregimens uncontrollednaturalhistory earlydiagnosisconfounding; raredeficiency nothealthyadultenhancement

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[58] Advancing clinical insight into creatine transporter deficiency: long term outcome and new observations from the Italian cohort.

Shows: Italiantransporterdeficiency cohortdocumentspersistentlylowbraincreatine heterogeneousclinicalcourseandtreatment

Does not show: Arginineregimen uncontrolled raredevelopmentaldisease; no supplementefficacy inference

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[59] Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia.

Shows: HyperornithinemiaMRScohort shows lowbraincreatine partiallycorrectedbycreatine/precursors/diet

Does not show: Mixedtherapy andmetabolicdiseaseoutsidehealthyscope; no matchedcognitiveefficacy

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[60] Increase of total creatine in human brain after oral supplementation of creatine-monohydrate.

Shows: Six healthyvolunteers fourweek oralcreatine MRS shows reversible regional totaltissuecreatine increase

Does not show: Tiny uncontrolled exposurestudy; variable regionalresponse; targetengagement notcognitivebenefit

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[61] Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.

Shows: Double-blind 5-day trial reduces mentalfatigue and task-evoked cerebraloxygenation change

Does not show: NIRSnotcreatinemeasurement; fatigueandoxygenation concurrence doesnotdemonstrate mediation

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

Documentary record

Every grade on this site is reproducible from its record. The files below are the posted edition exactly as assessed.

• ADVERSARIAL_REVIEW.md
• CONSENSUS_CROSSCHECK.html
• CONSENSUS_CROSSCHECK.md
• RESEARCH_TIMELINE.html
• RESEARCH_TIMELINE.md
• SHA256.txt
• adversarial-findings.json
• codex-correction-provenance.json
• consensus-validation.json
• creatine-cognition.review.md
• creatine-cognition.scorecard.json
• edition-approval-audit.json
• reader-summary.json
• research-timeline.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt
• video-insert.md
• web-page.md

Sources: 61 · load-bearing claims: 66 · verified: 66 · unverified: 0 · contradicted: 0 · schema 5.3