{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.", "entry_form": "claim", "gradeable_restatement": "Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Otherwise healthy adult status, baseline age/sex/diet/sleep state, exposure formulation/dose/duration and fixed cognitive endpoints identifiable before outcome", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Creatine and Cognitive Performance", "central_claim": "Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.", "proposed_mechanism": "Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.", "claimed_scope": "Otherwise healthy adults, with baseline age, sex, dietary pattern, dose, formulation, exposure duration and rested versus experimentally sleep-deprived/hypoxic state fixed before outcomes. Inherited deficiency, Alzheimer disease, children, developmental animal interventions and intranasal/precursor delivery are explicit boundary or mechanism evidence, not healthy-adult efficacy trials.", "claimed_level": [ "response" ], "is_conjunctive": false, "conjunctive_note": "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." }, "rubric_routing": { "primary_rubric": "07-psychiatry-neuromodulation.md", "secondary_rubrics": [ "06-metabolism-aging.md" ], "index_notes_applied": [ "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." ], "rubric_fit_note": "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." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Oral creatine increases brain creatine availability and alters cerebral energy buffering.", "subclaim_type": "mechanism", "scope": "Adults without inherited creatine-deficiency syndromes; dose and exposure duration specified", "claimed_scope": "Adults without inherited creatine-deficiency syndromes; dose and exposure duration specified", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Brain spectroscopy and controlled energetic challenge", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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.", "rubric_adaptation": "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." }, { "id": "SC2", "statement": "Oral creatine improves cognitive performance against a credible comparator in otherwise healthy adults.", "subclaim_type": "sufficiency", "scope": "Otherwise healthy adults; prespecified cognitive domains and assessment horizon; sleep loss retained as a predefined modifier", "claimed_scope": "Otherwise healthy adults; prespecified cognitive domains and assessment horizon; sleep loss retained as a predefined modifier", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Controlled human cognitive outcomes, including null replication", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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.", "rubric_adaptation": "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." }, { "id": "SC3", "statement": "Cognitive benefits generalize across baseline age, sex, diet and sleep conditions.", "subclaim_type": "generalization", "scope": "Baseline age, sex, diet, sleep deprivation and exposure defined before outcomes; no responder-defined subgroup", "claimed_scope": "Baseline age, sex, diet, sleep deprivation and exposure defined before outcomes; no responder-defined subgroup", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Adequately powered stratification and direct interaction tests", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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.", "rubric_adaptation": "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." }, { "id": "SC4", "statement": "Brain creatine changes mediate the observed cognitive benefit.", "subclaim_type": "mechanism", "scope": "Same individuals, temporal ordering and mediator-specific tests; not muscle benefits or deficiency rescue", "claimed_scope": "Same individuals, temporal ordering and mediator-specific tests; not muscle benefits or deficiency rescue", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Mediator perturbation and paired brain/cognitive outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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.", "rubric_adaptation": "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." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "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.", "primary_subclaim_id": "SC2", "aggregation_derivation": "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.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Ε", "scope_matched_would_return": "Ε", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Baseline energetic demand modifies benefit", "core_claim": "Creatine has task-specific cognitive effects under experimentally measured energetic stress, with inconsistent benefits in ordinary rested conditions.", "explains_what_nominal_does_not": "Creatine has task-specific cognitive effects under experimentally measured energetic stress, with inconsistent benefits in ordinary rested conditions.", "strongest_supporting_evidence": [ "Sleep-loss and hypoxia trials provide positive cognitive contrasts while comprehensive rested-adult and older-women trials provide relevant negative boundaries." ], "strongest_contradictory_evidence": [ "Dietary and sex modifiers remain inconsistent; challenge studies are small and high doses cannot be generalized to everyday protocols." ], "hsef_level_for_this_model": "Ε", "rationale": "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_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Oral creatine improves cognitive performance", "core_claim": "Oral creatine causes improvement in some tested cognitive outcomes in otherwise healthy adults.", "explains_what_nominal_does_not": "Oral creatine causes improvement in some tested cognitive outcomes in otherwise healthy adults.", "strongest_supporting_evidence": [ "Controlled vegetarian, fatigue, sleep-loss and hypoxia studies retain genuine positive results." ], "strongest_contradictory_evidence": [ "The large preregistered trial finds only small uncertain effects, several domains are null, and stable daily-function benefit is untested." ], "hsef_level_for_this_model": "Ε", "rationale": "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_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Target engagement without reliable cognitive gain", "core_claim": "Brain creatine or energetic ratios can move without a measurable cognitive improvement; brain and muscle handling differ.", "explains_what_nominal_does_not": "Brain creatine or energetic ratios can move without a measurable cognitive improvement; brain and muscle handling differ.", "strongest_supporting_evidence": [ "MRS protocols show exposure-specific and sometimes null brain responses; young-adult dose trials find no cognition/fNIRS gain." ], "strongest_contradictory_evidence": [ "Some paired stress-challenge studies show both engagement and performance, so this cannot explain every positive cognitive contrast." ], "hsef_level_for_this_model": "Γ", "rationale": "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_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Expectancy and practice account for apparent gain", "core_claim": "Repeated testing, imperfect blinding and participant expectations generate some apparent improvements.", "explains_what_nominal_does_not": "Repeated testing, imperfect blinding and participant expectations generate some apparent improvements.", "strongest_supporting_evidence": [ "Trial order/practice effects, solubility differences, selected outcomes and uncontrolled pilot improvements supply credible confounders." ], "strongest_contradictory_evidence": [ "No examined trial experimentally isolated expectancy as the sufficient cause; blinded positive contrasts prevent a blanket placebo-only verdict." ], "hsef_level_for_this_model": "Β", "rationale": "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." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. 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.", "study_separating_rank1_from_rank2": "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.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "40854087", "title": "The Effects of 8-Week Creatine Hydrochloride and Creatine Ethyl Ester Supplementation on Cognition, Clinical Outcomes, and Brain Creatine Levels in Perimenopausal and Menopausal Women (CONCRET-MENOPA): A Randomized Controlled Trial.", "citation": "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.", "doi": "10.1080/27697061.2025.2551184", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40854087/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40854087/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40854087", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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The effects of creatine supplementation on cognitive performance-a randomised controlled study. BMC medicine. 2023.", "doi": "10.1186/s12916-023-03146-5", "pmcid": "PMC10647179", "url": "https://pubmed.ncbi.nlm.nih.gov/37968687/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37968687/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37968687", "access_depth": "full_text_partial", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M2", "M3", "M4" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Preregistered 123-person crossover finds small uncertain working-memory effect no clear reasoning or exploratory-task benefit and no diet interaction", "what_it_does_not_show": "Incomplete blinding assessment; order/practice effects; powered for larger effects not definitive exclusion of small benefit", "confounders_present": [ "Incomplete blinding assessment; order/practice effects; powered for larger effects not definitive exclusion of small benefit" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 3, "pmid": "17828627", "title": "Creatine supplementation and cognitive performance in elderly individuals.", "citation": "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.", "doi": "10.1080/13825580600788100", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17828627/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17828627/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID17828627", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Short elderly controlled loading trial reports several memory-task gains", "what_it_does_not_show": "32 participants short duration placebo-first sequence and multiple outcomes; no brain mediator", "confounders_present": [ "32 participants short duration placebo-first sequence and multiple outcomes; no brain mediator" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 4, "pmid": "16416332", "title": "Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol.", "citation": "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.", "doi": "10.1007/s00213-005-0269-z", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16416332/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16416332/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID16416332", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Double-blind controlled 19-person sleep-loss challenge shows task-specific protection after 24 hours", "what_it_does_not_show": "Sleep loss plus exercise bundled; small sample multiple endpoints; no direct brain exposure measurement", "confounders_present": [ "Sleep loss plus exercise bundled; small sample multiple endpoints; no direct brain exposure measurement" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 5, "pmid": "17046034", "title": "Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior.", "citation": "McMorris T, Harris RC, Howard AN et al. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiology & behavior. 2007.", "doi": "10.1016/j.physbeh.2006.08.024", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17046034/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17046034/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID17046034", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Creatine improves complex central executive task at 36 hours sleep loss with most other outcomes unchanged", "what_it_does_not_show": "Restricted acute challenge; small trial; no general rested-adult inference", "confounders_present": [ "Restricted acute challenge; small trial; no general rested-adult inference" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 6, "pmid": "40758095", "title": "Acute creatine supplementation enhances technical performance in adolescent basketball players under cognitive-motor dual-task condition.", "citation": "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.", "doi": "10.1080/15502783.2025.2542369", "pmcid": "PMC12322996", "url": "https://pubmed.ncbi.nlm.nih.gov/40758095/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40758095/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40758095", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Adolescent athletic crossover improves some dual-task skill metrics and subtraction accuracy only during shooting", "what_it_does_not_show": "Children outside registered adult scope; muscle and technical-skill components cannot isolate cognitive enhancement", "confounders_present": [ "Children outside registered adult scope; muscle and technical-skill components cannot isolate cognitive enhancement" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 7, "pmid": "38542677", "title": "The Effect of Creatine Nitrate and Caffeine Individually or Combined on Exercise Performance and Cognitive Function: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.", "citation": "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.", "doi": "10.3390/nu16060766", "pmcid": "PMC10974193", "url": "https://pubmed.ncbi.nlm.nih.gov/38542677/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38542677/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID38542677", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Creatine-nitrate plus caffeine improves Stroop interference in 12 trained men", "what_it_does_not_show": "Combined formulation caffeine and nitrate prevent monohydrate-specific attribution; short exposure and small cohort", "confounders_present": [ "Combined formulation caffeine and nitrate prevent monohydrate-specific attribution; short exposure and small cohort" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 8, "pmid": "42075005", "title": "Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance.", "citation": "Gordji-Nejad A, Matusch A, Hengstler L et al. Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance. Nutrients. 2026.", "doi": "10.3390/nu18081192", "pmcid": "PMC13119191", "url": "https://pubmed.ncbi.nlm.nih.gov/42075005/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42075005/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42075005", "access_depth": "full_text_partial", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "29-person lower-dose sleep-loss crossover reports logical-task protection with heterogeneous corrected effects", "what_it_does_not_show": "Repeated-time pooled tests and multiple subgroup endpoints; primary LMM accounts clustering but headline percentages not universal benefit", "confounders_present": [ "Repeated-time pooled tests and multiple subgroup endpoints; primary LMM accounts clustering but headline percentages not universal benefit" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 9, "pmid": "21118604", "title": "The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.", "citation": "Benton D, Donohoe R. 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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.", "doi": "10.1080/15502783.2026.2716273", "pmcid": "PMC13463452", "url": "https://pubmed.ncbi.nlm.nih.gov/42578920/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42578920/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42578920", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "12-week randomized creatine component reports selected exploratory cognition and memory improvements in middle-aged adults", "what_it_does_not_show": "Exercise/diet participation self-selected; many cognitive endpoints explicitly exploratory;64 completers", "confounders_present": [ "Exercise/diet participation self-selected; many cognitive endpoints explicitly exploratory;64 completers" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 11, "pmid": "24098469", "title": "Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: a randomized double-blind study.", "citation": "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.", "doi": "10.1371/journal.pone.0076301", "pmcid": "PMC3789718", "url": "https://pubmed.ncbi.nlm.nih.gov/24098469/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24098469/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID24098469", "access_depth": "full_text_partial", "access_note": "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. 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Dose-Response of Creatine Supplementation on Cognitive Function in Healthy Young Adults. Brain sciences. 2023.", "doi": "10.3390/brainsci13091276", "pmcid": "PMC10526554", "url": "https://pubmed.ncbi.nlm.nih.gov/37759877/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37759877/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37759877", "access_depth": "full_text_partial", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [ "M2", "M4" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Six-week 10/20 g randomized trial finds no cognitive-domain or PFC oxygenation effect", "what_it_does_not_show": "30 participants powered for large effect; fNIRS not brain creatine; uncertain small effects remain", "confounders_present": [ "30 participants powered for large effect; fNIRS not brain creatine; uncertain small effects remain" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 13, "pmid": "25632150", "title": "Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation.", "citation": "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.", "doi": "10.1523/JNEUROSCI.3113-14.2015", "pmcid": "PMC6795258", "url": "https://pubmed.ncbi.nlm.nih.gov/25632150/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25632150/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID25632150", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "15-person hypoxic crossover reports brain creatine increase and restored attention during oxygen deficit", "what_it_does_not_show": "Severe acute hypoxia not ordinary rested cognition; mediator presumed not blocked; original body unavailable", "confounders_present": [ "Severe acute hypoxia not ordinary rested cognition; mediator presumed not blocked; original body unavailable" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 14, "pmid": "41470776", "title": "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.", "citation": "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.", "doi": "10.3390/nu17243831", "pmcid": "PMC12736258", "url": "https://pubmed.ncbi.nlm.nih.gov/41470776/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41470776/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41470776", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "14 active men crossover reports better digit-cancellation performance and subjective sleep", "what_it_does_not_show": "Objective sleep and many recovery measures unchanged; task multiplicity short loading and exercise context", "confounders_present": [ "Objective sleep and many recovery measures unchanged; task multiplicity short loading and exercise context" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 15, "pmid": "41941966", "title": "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.", "citation": "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.", "doi": "10.1016/j.exger.2026.113122", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41941966/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41941966/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41941966", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Older-adult sixarm trial reports training effects and creatine additions mainly on strength/function and biomarkers", "what_it_does_not_show": "Abstract does not establish an isolated creatine cognitive contrast; exercise gains cannot be credited to supplement", "confounders_present": [ "Abstract does not establish an isolated creatine cognitive contrast; exercise gains cannot be credited to supplement" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 16, "pmid": "31403610", "title": "Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills?", "citation": "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.", "doi": "10.1249/MSS.0000000000002122", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31403610/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31403610/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID31403610", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "14-person mental-fatigue crossover improves prolonged Stroop accuracy but fails to prevent short visuomotor/Flanker decline", "what_it_does_not_show": "Task-specific gains and physical-strength effects; no mediator measurement", "confounders_present": [ "Task-specific gains and physical-strength effects; no mediator measurement" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 17, "pmid": "18579168", "title": "Creatine supplementation does not improve cognitive function in young adults.", "citation": "Rawson ES, Lieberman HR, Walsh TM et al. Creatine supplementation does not improve cognitive function in young adults. Physiology & behavior. 2008.", "doi": "10.1016/j.physbeh.2008.05.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18579168/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18579168/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID18579168", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "22-person sixweek placebo trial finds no benefit across comprehensive youngadult neurocognitive tests", "what_it_does_not_show": "Small cohort modest dose; null does not exclude all doses/domains or stress contexts", "confounders_present": [ "Small cohort modest dose; null does not exclude all doses/domains or stress contexts" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 18, "pmid": "42730704", "title": "Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults.", "citation": "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.", "doi": "10.1080/15502783.2026.2711032", "pmcid": "PMC13573532", "url": "https://pubmed.ncbi.nlm.nih.gov/42730704/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42730704/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42730704", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "GAA with or without creatine trial finds selected retrieval-speed changes and numerous null cognitive domains", "what_it_does_not_show": "No creatine-only arm; many outcomes and near-significance findings; precursor attribution differs", "confounders_present": [ "No creatine-only arm; many outcomes and near-significance findings; precursor attribution differs" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 19, "pmid": "38418482", "title": "Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.", "citation": "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.", "doi": "10.1038/s41598-024-54249-9", "pmcid": "PMC10902318", "url": "https://pubmed.ncbi.nlm.nih.gov/38418482/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38418482/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "GordjiNejad_highdose_sleep2024", "access_depth": "full_text_partial", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [ "M1", "M2" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "15-person randomized sleep-loss crossover links acute high-dose creatine to metabolic changes and cognitive preservation", "what_it_does_not_show": "Paired changes/correlations do not manipulate mediator; pooled timepoints and many voxel/endpoints; specialized high-dose challenge", "confounders_present": [ "Paired changes/correlations do not manipulate mediator; pooled timepoints and many voxel/endpoints; specialized high-dose challenge" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 20, "pmid": "28397310", "title": "Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats.", "citation": "Dworak M, Kim T, Mccarley RW et al. Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats. Journal of sleep research. 2017.", "doi": "10.1111/jsr.12523", "pmcid": "PMC5435551", "url": "https://pubmed.ncbi.nlm.nih.gov/28397310/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28397310/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID28397310", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Rat oral supplementation alters sleep pressure adenosine and brain energetic measurements", "what_it_does_not_show": "No human cognition; ATP decreases and PCr trend prevent simple moreATP account", "confounders_present": [ "No human cognition; ATP decreases and PCr trend prevent simple moreATP account" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "40520504", "title": "Hemispheric asymmetry in high-energy phosphate consumption during sleep-deprivation is balanced by creatine.", "citation": "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.", "doi": "10.3389/fnins.2025.1515761", "pmcid": "PMC12162656", "url": "https://pubmed.ncbi.nlm.nih.gov/40520504/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40520504/", "tier": "A", "source_tier": "A", "kind": "secondary_analysis", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "GordjiNejad_highdose_sleep2024", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Reanalysis of 2024 sleep-loss dataset reports creatine effects on hemispheric phosphate asymmetry", "what_it_does_not_show": "Same 15 participants as PMID38418482 not independent trial; metabolite ratios not cognitive mediation", "confounders_present": [ "Same 15 participants as PMID38418482 not independent trial; metabolite ratios not cognitive mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "same 15-person trial as PMID38418482" ] }, { "n": 22, "pmid": "32439266", "title": "Guanidinoacetic acid loading for improved location-specific brain creatine.", "citation": "Ostojic SM. Guanidinoacetic acid loading for improved location-specific brain creatine. Clinical nutrition (Edinburgh, Scotland). 2021.", "doi": "10.1016/j.clnu.2020.05.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32439266/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32439266/", "tier": "A", "source_tier": "A", "kind": "secondary_analysis", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "GAA_loading_participant_overlap_unresolved", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Secondary GAA-loading analysis reports location-dependent brain creatine increases and thalamic decrease", "what_it_does_not_show": "Precursor not oral creatine; responder categorization postoutcome cannot define registered beneficiary scope; pooled source trials", "confounders_present": [ "Precursor not oral creatine; responder categorization postoutcome cannot define registered beneficiary scope; pooled source trials" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "secondary pooled GAA loading; participant overlap with prior GAA report not fully resolved" ] }, { "n": 23, "pmid": "42061673", "title": "Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.", "citation": "Ostojic SM, Ostojic J. Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study. Neuroscience letters. 2026.", "doi": "10.1016/j.neulet.2026.138616", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42061673/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42061673/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42061673", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Exploratory 12-woman MRS study correlates regional brain creatine with concentration complaints and estradiol", "what_it_does_not_show": "No supplementation randomization; reference-age comparison and multiple correlations; no causal menopause mechanism", "confounders_present": [ "No supplementation randomization; reference-age comparison and multiple correlations; no causal menopause mechanism" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 24, "pmid": "42479961", "title": "Real-world creatine supplementation: a large-scale cross-sectional study of use, knowledge, and experiences.", "citation": "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.", "doi": "10.1080/15502783.2026.2702952", "pmcid": "PMC13390171", "url": "https://pubmed.ncbi.nlm.nih.gov/42479961/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42479961/", "tier": "A", "source_tier": "A", "kind": "survey", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42479961", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Supplement-user survey records strong loyalty but frequent unmet cognitive expectations and sex differences", "what_it_does_not_show": "Selfselected app respondents selfreported exposure/outcomes no untreated comparator; cannot estimate efficacy or causal adverse-event incidence", "confounders_present": [ "Selfselected app respondents selfreported exposure/outcomes no untreated comparator; cannot estimate efficacy or causal adverse-event incidence" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 25, "pmid": "33866527", "title": "Dietary creatine and cognitive function in U.S. adults aged 60 years and over.", "citation": "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.", "doi": "10.1007/s40520-021-01857-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33866527/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33866527/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID33866527", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NHANES older-adult dietary creatine estimate correlates weakly with digit-symbol scores", "what_it_does_not_show": "Food pattern recall education and health confounding; not supplemental-creatine intervention", "confounders_present": [ "Food pattern recall education and health confounding; not supplemental-creatine intervention" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 26, "pmid": "40395689", "title": "Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition.", "citation": "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.", "doi": "10.1002/trc2.70101", "pmcid": "PMC12089086", "url": "https://pubmed.ncbi.nlm.nih.gov/40395689/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40395689/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NCT05383833_ADpilot", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "20-person uncontrolled Alzheimer pilot reports 11 percent brain creatine increase and improved repeated tests", "what_it_does_not_show": "Disease outside healthy scope; singlearm practice/regression effects; not efficacy or mediation proof", "confounders_present": [ "Disease outside healthy scope; singlearm practice/regression effects; not efficacy or mediation proof" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 27, "pmid": "14561278", "title": "Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.", "citation": "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.", "doi": "10.1098/rspb.2003.2492", "pmcid": "PMC1691485", "url": "https://pubmed.ncbi.nlm.nih.gov/14561278/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14561278/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID14561278", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M1", "M2" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "45 vegetarian adults crossover reports large backward-digit and Raven gains with 5 g/day six weeks", "what_it_does_not_show": "No brain exposure measurement; vegetarian-only recruitment cannot establish diet interaction; large effects not reproduced by 123-person trial", "confounders_present": [ "No brain exposure measurement; vegetarian-only recruitment cannot establish diet interaction; large effects not reproduced by 123-person trial" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 28, "pmid": "37429386", "title": "Intranasal creatine administration increases brain creatine level and improves Barnes maze performance in rats.", "citation": "Chen K, Hu X. Intranasal creatine administration increases brain creatine level and improves Barnes maze performance in rats. Brain research bulletin. 2023.", "doi": "10.1016/j.brainresbull.2023.110703", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37429386/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37429386/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37429386", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Rat intranasal route increases regional brain creatine and Barnes performance more than oral route", "what_it_does_not_show": "Intranasal research delivery is not oral human supplement; behavioral/exposure concurrence not isolated energy mediation", "confounders_present": [ "Intranasal research delivery is not oral human supplement; behavioral/exposure concurrence not isolated energy mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 29, "pmid": "39792585", "title": "A creatine efflux transporter in oligodendrocytes.", "citation": "Flögel S, Strater M, Fischer D et al. A creatine efflux transporter in oligodendrocytes. The FEBS journal. 2025.", "doi": "10.1111/febs.17382", "pmcid": "PMC11880989", "url": "https://pubmed.ncbi.nlm.nih.gov/39792585/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39792585/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID39792585", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Heterologous transporter assays identify conditional SLC22A15 creatine efflux with oligodendrocyte expression", "what_it_does_not_show": "Expression and cell efflux do not establish healthy-adult oral brain uptake or cognitive mediation", "confounders_present": [ "Expression and cell efflux do not establish healthy-adult oral brain uptake or cognitive mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 30, "pmid": "32990357", "title": "Oxidative phosphorylation in creatine transporter deficiency.", "citation": "Li S, Bianconi S, van der Veen JW et al. Oxidative phosphorylation in creatine transporter deficiency. NMR in biomedicine. 2021.", "doi": "10.1002/nbm.4419", "pmcid": "PMC7722185", "url": "https://pubmed.ncbi.nlm.nih.gov/32990357/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32990357/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID32990357", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Transporter-deficiency phosphorusMRS shows low PCr/creatine despite preserved oxidative-energy indices", "what_it_does_not_show": "Congenital disease not healthy enhancement; developmental compensation; low creatine not simple globalATP failure", "confounders_present": [ "Congenital disease not healthy enhancement; developmental compensation; low creatine not simple globalATP failure" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 31, "pmid": "40729420", "title": "Connectomic and behavioural alterations in creatine transporter deficiency are partially normalized by gene therapy.", "citation": "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.", "doi": "10.1093/brain/awaf275", "pmcid": "PMC13016649", "url": "https://pubmed.ncbi.nlm.nih.gov/40729420/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40729420/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40729420", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Perinatal gene restoration in transporterKO partly rescues networks and memory but leaves deficits and harms wildtype cognition", "what_it_does_not_show": "Developmental ectopic gene therapy; not oralcreatine healthy-adult necessity/sufficiency; incomplete rescue", "confounders_present": [ "Developmental ectopic gene therapy; not oralcreatine healthy-adult necessity/sufficiency; incomplete rescue" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 32, "pmid": "37814487", "title": "Creatine mapping of the brain at 3T by CEST MRI.", "citation": "Wang K, Huang J, Ju L et al. Creatine mapping of the brain at 3T by CEST MRI. Magnetic resonance in medicine. 2024.", "doi": "10.1002/mrm.29876", "pmcid": "PMC10843037", "url": "https://pubmed.ncbi.nlm.nih.gov/37814487/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37814487/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37814487", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "GAMT knockout and wildtype comparisons establish creatine and pH contributions to CEST signal", "what_it_does_not_show": "Readout calibration only; CEST contains proteinarginine contribution and is not a pure cognitive mediator", "confounders_present": [ "Readout calibration only; CEST contains proteinarginine contribution and is not a pure cognitive mediator" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 33, "pmid": "33389772", "title": "Creatine transport and pathological changes in creatine transporter deficient mice.", "citation": "Wawro AM, Gajera CR, Baker SA et al. Creatine transport and pathological changes in creatine transporter deficient mice. Journal of inherited metabolic disease. 2021.", "doi": "10.1002/jimd.12358", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33389772/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33389772/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID33389772", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "TransporterKO study measures organ-specific labeled creatine uptake and pathology", "what_it_does_not_show": "Severe congenital model and peripheral disease do not identify normaladult cognitive supplement response", "confounders_present": [ "Severe congenital model and peripheral disease do not identify normaladult cognitive supplement response" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 34, "pmid": "34324436", "title": "Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis.", "citation": "Chen HR, Zhang-Brotzge X, Morozov YM et al. Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis. JCI insight. 2021.", "doi": "10.1172/jci.insight.140173", "pmcid": "PMC8492331", "url": "https://pubmed.ncbi.nlm.nih.gov/34324436/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34324436/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID34324436", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Female mice heterozygous for creatine transporter deficiency show moderate cognitive deficits. Journal of inherited metabolic disease. 2014.", "doi": "10.1007/s10545-013-9619-x", "pmcid": "PMC7025435", "url": "https://pubmed.ncbi.nlm.nih.gov/23716276/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23716276/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID23716276", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Bioenergetic data from a creatine monohydrate pilot trial in Alzheimer's disease. Alzheimer's & dementia (New York, N. Y.). 2026.", "doi": "10.1002/trc2.70228", "pmcid": "PMC12927926", "url": "https://pubmed.ncbi.nlm.nih.gov/41737290/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41737290/", "tier": "A", "source_tier": "A", "kind": "secondary_analysis", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NCT05383833_ADpilot", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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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.", "doi": "10.1097/01.jsm.0000176372.67398.c8", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16377978/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16377978/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID16377978", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Athlete placeboMRScomparison findsno deepfrontalwhitemattercreatinemovement after 5-day loading", "what_it_does_not_show": "Small 18-person regionalstudy shortprotocol; no cognitiveendpoint", "confounders_present": [ "Small 18-person regionalstudy shortprotocol; no cognitiveendpoint" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 55, "pmid": "28572496", "title": "Effect of age, diet, and tissue type on PCr response to creatine supplementation.", "citation": "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.", "doi": "10.1152/japplphysiol.00248.2017", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28572496/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28572496/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID28572496", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Rat oralMRSstudy reports modestbraincreatine/metabolismchanges withoutchangedischemiclactatecourse", "what_it_does_not_show": "Species andhigh-dose; metabolicphenotype notfunctional cognitivebenefit", "confounders_present": [ "Species andhigh-dose; metabolicphenotype notfunctional cognitivebenefit" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 57, "pmid": "24268530", "title": "Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.", "citation": "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.", "doi": "10.1016/j.ymgme.2013.10.018", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24268530/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24268530/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID24268530", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "GAMT48-patient cohort finds cerebralcreatine restorationand betterearlytreateddevelopmentaloutcomes", "what_it_does_not_show": "Combinedregimens uncontrollednaturalhistory earlydiagnosisconfounding; raredeficiency nothealthyadultenhancement", "confounders_present": [ "Combinedregimens uncontrollednaturalhistory earlydiagnosisconfounding; raredeficiency nothealthyadultenhancement" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 58, "pmid": "41776642", "title": "Advancing clinical insight into creatine transporter deficiency: long term outcome and new observations from the Italian cohort.", "citation": "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.", "doi": "10.1186/s13023-026-04289-3", "pmcid": "PMC13063627", "url": "https://pubmed.ncbi.nlm.nih.gov/41776642/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41776642/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41776642", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Italiantransporterdeficiency cohortdocumentspersistentlylowbraincreatine heterogeneousclinicalcourseandtreatment", "what_it_does_not_show": "Arginineregimen uncontrolled raredevelopmentaldisease; no supplementefficacy inference", "confounders_present": [ "Arginineregimen uncontrolled raredevelopmentaldisease; no supplementefficacy inference" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 59, "pmid": "10430418", "title": "Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia.", "citation": "Nänto-Salonen K, Komu M, Lundbom N et al. Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology. 1999.", "doi": "10.1212/wnl.53.2.303", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10430418/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10430418/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID10430418", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "HyperornithinemiaMRScohort shows lowbraincreatine partiallycorrectedbycreatine/precursors/diet", "what_it_does_not_show": "Mixedtherapy andmetabolicdiseaseoutsidehealthyscope; no matchedcognitiveefficacy", "confounders_present": [ "Mixedtherapy andmetabolicdiseaseoutsidehealthyscope; no matchedcognitiveefficacy" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 60, "pmid": "10484486", "title": "Increase of total creatine in human brain after oral supplementation of creatine-monohydrate.", "citation": "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.", "doi": "10.1152/ajpregu.1999.277.3.R698", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10484486/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10484486/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID10484486", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Six healthyvolunteers fourweek oralcreatine MRS shows reversible regional totaltissuecreatine increase", "what_it_does_not_show": "Tiny uncontrolled exposurestudy; variable regionalresponse; targetengagement notcognitivebenefit", "confounders_present": [ "Tiny uncontrolled exposurestudy; variable regionalresponse; targetengagement notcognitivebenefit" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 61, "pmid": "11985880", "title": "Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation.", "citation": "Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neuroscience research. 2002.", "doi": "10.1016/s0168-0102(02)00007-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11985880/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11985880/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID11985880", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Double-blind 5-day trial reduces mentalfatigue and task-evoked cerebraloxygenation change", "what_it_does_not_show": "NIRSnotcreatinemeasurement; fatigueandoxygenation concurrence doesnotdemonstrate mediation", "confounders_present": [ "NIRSnotcreatinemeasurement; fatigueandoxygenation concurrence doesnotdemonstrate mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 66, "verified": 66, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "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.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "**Mediation-by-correlation rule.** Candidate mediator correlated with outcome, never manipulated.", "specific_trigger": "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.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Oral creatine supplementation causes an improvement in cognitive performance in otherwise healthy adults.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "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.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Biomarker change without functional/phenotypic change caps at Γ. Applied to brain target-engagement inference; clinical cognitive outcomes are assessed separately under SC2." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID16416332, PMID17046034, PMID42075005, PMID21118604, PMID25632150, PMID41470776, PMID38418482, PMID14561278, PMID11985880", "gamma_hard_rules_triggered": [ "No literal hallucination-related unblinding rule; placebo matching, allocation guesses, test multiplicity and repeated-time analyses limit confidence." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "No positive universal causal crossing. Nulls and heterogeneous controlled results constrain generalization without recoding the entire set as association-only." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Candidate mediator correlated with outcome, never manipulated." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "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." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "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", "supporting_evidence": [ "[4] Double-blind controlled 19-person sleep-loss challenge shows task-specific protection after 24 hours", "[5] Creatine improves complex central executive task at 36 hours sleep loss with most other outcomes unchanged", "[8] 29-person lower-dose sleep-loss crossover reports logical-task protection with heterogeneous corrected effects", "[9] 128 women double-blind trial reports vegetarian-specific memory gain and response-variability improvement", "[13] 15-person hypoxic crossover reports brain creatine increase and restored attention during oxygen deficit", "[14] 14 active men crossover reports better digit-cancellation performance and subjective sleep", "[19] 15-person randomized sleep-loss crossover links acute high-dose creatine to metabolic changes and cognitive preservation", "[27] 45 vegetarian adults crossover reports large backward-digit and Raven gains with 5 g/day six weeks", "[61] Double-blind 5-day trial reduces mentalfatigue and task-evoked cerebraloxygenation change" ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "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", "supporting_evidence": [ "[4] Double-blind controlled 19-person sleep-loss challenge shows task-specific protection after 24 hours", "[5] Creatine improves complex central executive task at 36 hours sleep loss with most other outcomes unchanged", "[8] 29-person lower-dose sleep-loss crossover reports logical-task protection with heterogeneous corrected effects", "[9] 128 women double-blind trial reports vegetarian-specific memory gain and response-variability improvement", "[13] 15-person hypoxic crossover reports brain creatine increase and restored attention during oxygen deficit", "[14] 14 active men crossover reports better digit-cancellation performance and subjective sleep", "[19] 15-person randomized sleep-loss crossover links acute high-dose creatine to metabolic changes and cognitive preservation", "[27] 45 vegetarian adults crossover reports large backward-digit and Raven gains with 5 g/day six weeks", "[61] Double-blind 5-day trial reduces mentalfatigue and task-evoked cerebraloxygenation change" ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent multi-site replication by sponsor-independent teams, pre-registered, without outcome switching\n- Blinding-integrity reporting in each replicating trial\n- One result narrowing the mechanism against expectancy: mediator manipulation, blinded dose-response, or non-subjective congener", "satisfied": "no", "supporting_evidence": [ "[4] Double-blind controlled 19-person sleep-loss challenge shows task-specific protection after 24 hours", "[5] Creatine improves complex central executive task at 36 hours sleep loss with most other outcomes unchanged", "[8] 29-person lower-dose sleep-loss crossover reports logical-task protection with heterogeneous corrected effects", "[9] 128 women double-blind trial reports vegetarian-specific memory gain and response-variability improvement", "[13] 15-person hypoxic crossover reports brain creatine increase and restored attention during oxygen deficit", "[14] 14 active men crossover reports better digit-cancellation performance and subjective sleep", "[19] 15-person randomized sleep-loss crossover links acute high-dose creatine to metabolic changes and cognitive preservation", "[27] 45 vegetarian adults crossover reports large backward-digit and Raven gains with 5 g/day six weeks", "[61] Double-blind 5-day trial reduces mentalfatigue and task-evoked cerebraloxygenation change" ], "what_would_cross_it": "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." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "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", "supporting_evidence": [], "what_would_cross_it": "Demonstrate replicated baseline-by-treatment interactions across age, sex, diet and sleep states with multiplicity control and measured preintervention brain creatine." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "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", "supporting_evidence": [], "what_would_cross_it": "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." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "PMID37759877: randomized 10/20 g doses leave tested cognition and fNIRS unchanged.", "PMID24098469: older-women cognition remains unchanged despite exercise effects on mood/strength.", "PMID37968687: preregistered diet interaction and exploratory cognition largely null.", "PMID28572496: muscle PCr response without brain PCr response.", "PMID22751104: cyclocreatine but not creatine rescues transporterKO cognition." ], "note": "Age, sex, dietary pattern, sleep deprivation, acute hypoxia, dose and delivery route are antecedent-defined modifiers. Positive stress experiments and rested/older-women nulls map a broad context boundary. They do not establish a deterministic responder rule, and no participants are retrospectively excluded as outside scope. Children, rare deficiencies and AD are examined only as transport/biological boundaries." }, "falsification_patterns_met": [], "pitfalls_flagged": [ { "pitfall": "Therapeutic effect misread as mechanistic proof", "where": "Paired cognitive/MRS changes do not show energetic mediation; congenital rescue does not establish healthy-adult enhancement." }, { "pitfall": "Selective generalization", "where": "Sleep-loss, hypoxia, vegetarians, menopause, children and animals require antecedent-defined scopes." }, { "pitfall": "Confirmation by biomarker", "where": "Regional creatine or phosphate ratios and fNIRS must not substitute for cognition or clinical function." }, { "pitfall": "Causal-evidence tallies that do not survive an audit", "where": "Negative trials, duplicate analyses, GAA combinations, single-arm pilots and out-of-scope animal studies do not count as positive healthy-adult efficacy crossings." }, { "pitfall": "Scope fitted to the result", "where": "No responder-defined narrowing or significant-within-subgroup rule is allowed." } ], "causal_tally_audit": { "tally_claimed_by_document": 5, "tally_after_audit": 5, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 18, "items_rejected": [ "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." ] }, "steelman": { "case_one_rung_higher": "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_one_rung_lower": "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.", "which_rejected": "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.", "blocking_cap_threshold_or_missing_experiment": "Missing 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." }, "final_score": { "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "confidence_rationale": "61 primary reports with 5 selected partial-body examinations; evidence density, independent replication and heterogeneity of controls set the confidence; access depth and belief in correctness do not.", "rests_on_non_peer_reviewed_work": false, "rationale": "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." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "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.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "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.", "justification": "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": { "value": "Stable", "trigger": "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.", "justification": "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": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Ε", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "new_level": "Ε", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "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.", "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", "critical_control": "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_result": "Replicated between-group cognitive improvement at the registered horizon with a baseline-defined interaction and a dissociation showing specific brain energetic mediation", "falsifying_result": "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": [ { "name": "Gap 1", "statement": "The minimum cognitive effect that matters for everyday functioning has not been established by brief laboratory scores.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Preintervention absolute brain creatine, dietary pattern, sex and age need prospectively powered interaction tests; vegetarian status cannot substitute for low brain stores.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Dose and exposure comparisons should separate total creatine from PCr/ATP ratios and regional from whole-brain engagement.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "The mediator remains unmanipulated in healthy-adult human trials; paired changes are not evidence of necessity.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "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.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-12", "reviewer": "Codex", "evidence_base_note": "61 primary reports; literature cutoff 2026-10-12; source examination UTC date 2026-10-13; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite monthly limit was reached earlier in this session; no new Scite query or incoming citation-context audit is claimed for these cases. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "These topic families were selected from an editorial traffic-priority list. Selection was visible; no blind calibration or predetermined clinical verdict was preregistered." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "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." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "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." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "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." }, { "kind": "withdrawal_rechallenge", "available": true, "why_not_sufficient": "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." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "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." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 61, "claims_total": 66, "claims_verified": 66, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 61, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Small four-arm double-blind menopause trial reports reaction-time and frontal creatine gains at medium hydrochloride dose 36 participants multiple formulations endpoints; original body unavailable; regional engagement is not mediation", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C2", "text": "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", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C3", "text": "Short elderly controlled loading trial reports several memory-task gains 32 participants short duration placebo-first sequence and multiple outcomes; no brain mediator", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C4", "text": "Double-blind controlled 19-person sleep-loss challenge shows task-specific protection after 24 hours Sleep loss plus exercise bundled; small sample multiple endpoints; no direct brain exposure measurement", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C5", "text": "Creatine improves complex central executive task at 36 hours sleep loss with most other outcomes unchanged Restricted acute challenge; small trial; no general rested-adult inference", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C6", "text": "Adolescent athletic crossover improves some dual-task skill metrics and subtraction accuracy only during shooting Children outside registered adult scope; muscle and technical-skill components cannot isolate cognitive enhancement", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C7", "text": "Creatine-nitrate plus caffeine improves Stroop interference in 12 trained men Combined formulation caffeine and nitrate prevent monohydrate-specific attribution; short exposure and small cohort", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C8", "text": "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", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C9", "text": "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", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C10", "text": "12-week randomized creatine component reports selected exploratory cognition and memory improvements in middle-aged adults Exercise/diet participation self-selected; many cognitive endpoints explicitly exploratory;64 completers", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C11", "text": "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", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C12", "text": "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", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C13", "text": "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", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C14", "text": "14 active men crossover reports better digit-cancellation performance and subjective sleep Objective sleep and many recovery measures unchanged; task multiplicity short loading and exercise context", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C15", "text": "Older-adult sixarm trial reports training effects and creatine additions mainly on strength/function and biomarkers Abstract does not establish an isolated creatine cognitive contrast; exercise gains cannot be credited to supplement", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C16", "text": "14-person mental-fatigue crossover improves prolonged Stroop accuracy but fails to prevent short visuomotor/Flanker decline Task-specific gains and physical-strength effects; no mediator measurement", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C17", "text": "22-person sixweek placebo trial finds no benefit across comprehensive youngadult neurocognitive tests Small cohort modest dose; null does not exclude all doses/domains or stress contexts", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C18", "text": "GAA with or without creatine trial finds selected retrieval-speed changes and numerous null cognitive domains No creatine-only arm; many outcomes and near-significance findings; precursor attribution differs", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C19", "text": "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", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C20", "text": "Rat oral supplementation alters sleep pressure adenosine and brain energetic measurements No human cognition; ATP decreases and PCr trend prevent simple moreATP account", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C21", "text": "Reanalysis of 2024 sleep-loss dataset reports creatine effects on hemispheric phosphate asymmetry Same 15 participants as PMID38418482 not independent trial; metabolite ratios not cognitive mediation", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C22", "text": "Secondary GAA-loading analysis reports location-dependent brain creatine increases and thalamic decrease Precursor not oral creatine; responder categorization postoutcome cannot define registered beneficiary scope; pooled source trials", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C23", "text": "Exploratory 12-woman MRS study correlates regional brain creatine with concentration complaints and estradiol No supplementation randomization; reference-age comparison and multiple correlations; no causal menopause mechanism", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C24", "text": "Supplement-user survey records strong loyalty but frequent unmet cognitive expectations and sex differences Selfselected app respondents selfreported exposure/outcomes no untreated comparator; cannot estimate efficacy or causal adverse-event incidence", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C25", "text": "NHANES older-adult dietary creatine estimate correlates weakly with digit-symbol scores Food pattern recall education and health confounding; not supplemental-creatine intervention", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C26", "text": "20-person uncontrolled Alzheimer pilot reports 11 percent brain creatine increase and improved repeated tests Disease outside healthy scope; singlearm practice/regression effects; not efficacy or mediation proof", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C27", "text": "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", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C28", "text": "Rat intranasal route increases regional brain creatine and Barnes performance more than oral route Intranasal research delivery is not oral human supplement; behavioral/exposure concurrence not isolated energy mediation", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C29", "text": "Heterologous transporter assays identify conditional SLC22A15 creatine efflux with oligodendrocyte expression Expression and cell efflux do not establish healthy-adult oral brain uptake or cognitive mediation", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C30", "text": "Transporter-deficiency phosphorusMRS shows low PCr/creatine despite preserved oxidative-energy indices Congenital disease not healthy enhancement; developmental compensation; low creatine not simple globalATP failure", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C31", "text": "Perinatal gene restoration in transporterKO partly rescues networks and memory but leaves deficits and harms wildtype cognition Developmental ectopic gene therapy; not oralcreatine healthy-adult necessity/sufficiency; incomplete rescue", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C32", "text": "GAMT knockout and wildtype comparisons establish creatine and pH contributions to CEST signal Readout calibration only; CEST contains proteinarginine contribution and is not a pure cognitive mediator", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C33", "text": "TransporterKO study measures organ-specific labeled creatine uptake and pathology Severe congenital model and peripheral disease do not identify normaladult cognitive supplement response", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C34", "text": "Transporter loss worsens energetic stress adaptation and intranasalcreatine partially rescues injury Genotype neonatalinjury and intranasal route differ from oral healthyadult cognitive augmentation", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C35", "text": "Double-blind creatineethylester study reports improvements on several cognitive measures Different chemicalform and objective adherence lacking; original abstract lacks detailed sample/effect sizes", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C36", "text": "Controlled adult rat stress study finds oralcreatine preservation of memory LTP and arborization High 2 g/kg animaldose; stress model not normalhuman scope; mechanism explicitly unresolved", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C37", "text": "42 olderadults dietary intake correlates with Corsi and memory scores Small nonrandomized dietary study median splits nutritional confounding; no causal supplement contrast", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C38", "text": "Neuronal cell and pretreated hippocampalslice studies show protection against toxic oxidative/glutamate insults Millimolar culture exposure injury endpoints and scavenging not healthyhuman cognitive mediation", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C39", "text": "Maternalcreatine exposure produces lasting adult offspring excitability/LTP changes Developmental intervention and electrophysiological proxy no direct human cognitive endpoint", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C40", "text": "Creatine salts differ in uptake and anoxic synaptic protection after transporter impairment Modifiedsalts transportblock anoxia not oralmonohydrate normaladult benefit", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C41", "text": "Agedmouse oralcreatine study reports healthy-lifespan and neurobehavioral improvement Onebackground aging neurobehavioral outcomes do not demonstrate human longevity or dementia prevention", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C42", "text": "TransporterKO mice respond to cyclocreatine with cognitive rescue while creatine fails Differentanalog congenital defect; supports transport boundary not ordinaryoralcreatine enhancement", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C43", "text": "Five men GAA series shows regional braincreatine gains but thalamic pattern differs Uncontrolled precursor dosing not oralcreatine cognition; possible overlap with secondaryGAA analyses", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C44", "text": "Creatine/PCr neuronalprotection experiments narrow secondaryglutamate but do not show dietary suppression of mitochondrial permeability transition Culturedinjury and isolatedmitochondria not cognitive mediator; proposed mitochondrial explanation has internal negativecontrol", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C45", "text": "19-person randomized creatineGAA combination changes prefrontaloxygenation atrest/recovery Combinedprecursor attribution and oxygenbiomarker not measured cognitive benefit or creatine mediation", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C46", "text": "Male/female rat watermaze trial finds practice-related workingmemory improvement independentofcreatine Animaltask and smallgroups; negativecontrol for automatic memoryenhancement not definitive human null", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C47", "text": "Ratbrain slices show electricallyevoked calcium/TTX-sensitive creatinerelease Neuromodulator plausibility not demonstrated contributionto supplement-associatedhumancognition", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C48", "text": "Female transporterheterozygote mice have selective memorydeficits with otherdomains spared Congenital Xlinkedmosaic context no supplementcontrast; not universal necessity in healthyadults", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C49", "text": "Seven-day humanMRS protocol altersbraincreatine and PCr/ATP ratio largelythroughdecreasedATP Energeticratio change not uniformlyincreasedATP or cognitivephenotype; no mediationmanipulation", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C50", "text": "Clonedhumansodiumdependent transporter demonstrates creatineuptake and analoguecompetition Heterologouscelluptake doesnot prove brainoralexposure or healthycognitivebenefit", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C51", "text": "SecondaryAlzheimerpilot reports peripheral energychanges but brainNAA/GSH remainunchanged Same NCT05383833 cohort as PMID40395689; uncontrolled and outofhealthyscope; peripheralmovement notbrainmediation", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C52", "text": "Conditional/endogenous GAMTdeletion delaysoligodendrocytematuration with remyelination benefitfromcreatineanalogues Developmental/remyelination contexts not healthyadult cognition; distinct cellularroles beyondsimpleATP boost", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C53", "text": "Healthychildren randomizedsupplementation shows neither regionalbraincreatine nor cognitiveimprovement Childrenoutsideadultscope; selectedMRSsubsample; short 7-day protocol", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C54", "text": "Athlete placeboMRScomparison findsno deepfrontalwhitemattercreatinemovement after 5-day loading Small 18-person regionalstudy shortprotocol; no cognitiveendpoint", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C55", "text": "Age/diet/tissue study finds musclePCr rise butno brainPCr response inalltestedgroups Singleblind placebo-first design andPCr not totaltissuecreatine; no cognitiveoutcomes; tissue-specificbaselineeffects", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C56", "text": "Rat oralMRSstudy reports modestbraincreatine/metabolismchanges withoutchangedischemiclactatecourse Species andhigh-dose; metabolicphenotype notfunctional cognitivebenefit", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C57", "text": "GAMT48-patient cohort finds cerebralcreatine restorationand betterearlytreateddevelopmentaloutcomes Combinedregimens uncontrollednaturalhistory earlydiagnosisconfounding; raredeficiency nothealthyadultenhancement", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C58", "text": "Italiantransporterdeficiency cohortdocumentspersistentlylowbraincreatine heterogeneousclinicalcourseandtreatment Arginineregimen uncontrolled raredevelopmentaldisease; no supplementefficacy inference", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C59", "text": "HyperornithinemiaMRScohort shows lowbraincreatine partiallycorrectedbycreatine/precursors/diet Mixedtherapy andmetabolicdiseaseoutsidehealthyscope; no matchedcognitiveefficacy", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C60", "text": "Six healthyvolunteers fourweek oralcreatine MRS shows reversible regional totaltissuecreatine increase Tiny uncontrolled exposurestudy; variable regionalresponse; targetengagement notcognitivebenefit", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "C61", "text": "Double-blind 5-day trial reduces mentalfatigue and task-evoked cerebraloxygenation change NIRSnotcreatinemeasurement; fatigueandoxygenation concurrence doesnotdemonstrate mediation", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC1", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 13, 19, 20, 21, 22, 23, 26, 28, 29, 30, 31, 32, 33, 34, 38, 39, 40, 42, 43, 44, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC2", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 27, 35, 36, 37, 41, 46, 53, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC3", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 31, 33, 34, 35, 36, 37, 39, 41, 42, 43, 46, 48, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC4", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 7, 12, 13, 18, 19, 20, 21, 23, 26, 28, 29, 30, 31, 32, 34, 36, 38, 39, 40, 41, 42, 44, 45, 47, 48, 49, 50, 51, 52, 53, 56, 57, 58, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CH", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 2, 19, 8, 13, 11, 12 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-13", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Korovljev D, Ostojic J, Panic J et al. 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Journal of the International Society of Sports Nutrition. 2026.", "tier": "A", "kind": "rct", "pmid": "42578920", "doi": "10.1080/15502783.2026.2716273", "url": "https://pubmed.ncbi.nlm.nih.gov/42578920/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42578920", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C10", "CSC2", "CSC3" ] }, { "n": 11, "citation": "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. 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Dose-Response of Creatine Supplementation on Cognitive Function in Healthy Young Adults. Brain sciences. 2023.", "tier": "A", "kind": "primary", "pmid": "37759877", "doi": "10.3390/brainsci13091276", "url": "https://pubmed.ncbi.nlm.nih.gov/37759877/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37759877", "access_depth": "full_text_partial", "access_note": "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.", "carries_claims": [ "C12", "CSC2", "CSC3", "CSC4", "CH" ] }, { "n": 13, "citation": "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.", "tier": "A", "kind": "rct", "pmid": "25632150", "doi": "10.1523/JNEUROSCI.3113-14.2015", "url": "https://pubmed.ncbi.nlm.nih.gov/25632150/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID25632150", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C13", "CSC1", "CSC2", "CSC3", "CSC4", "CH" ] }, { "n": 14, "citation": "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.", "tier": "A", "kind": "rct", "pmid": "41470776", "doi": "10.3390/nu17243831", "url": "https://pubmed.ncbi.nlm.nih.gov/41470776/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41470776", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C14", "CSC2", "CSC3" ] }, { "n": 15, "citation": "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.", "tier": "A", "kind": "rct", "pmid": "41941966", "doi": "10.1016/j.exger.2026.113122", "url": "https://pubmed.ncbi.nlm.nih.gov/41941966/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41941966", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C15", "CSC2", "CSC3" ] }, { "n": 16, "citation": "VAN Cutsem J, Roelands B, Pluym B et al. 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Journal of the International Society of Sports Nutrition. 2026.", "tier": "A", "kind": "rct", "pmid": "42730704", "doi": "10.1080/15502783.2026.2711032", "url": "https://pubmed.ncbi.nlm.nih.gov/42730704/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42730704", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C18", "CSC2", "CSC3", "CSC4" ] }, { "n": 19, "citation": "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. 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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_source": "https://pubmed.ncbi.nlm.nih.gov/40854087/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\examinations\\original-0-6-12000.json" ], "body_receipts": [] }, { "pmid": "24098469", "doi": "10.1371/journal.pone.0076301", "source_type": "primary study report", "study_group": "PMID24098469", "access_depth": "full_text_partial", "consensus_aspect": "Consensus broadly acknowledges null geriatric executive findings without detailing the 24-week older women factorial trial.", "result_comparison": "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_source": "https://pubmed.ncbi.nlm.nih.gov/24098469/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\examinations\\original-6-13-12000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\body-presentation-receipts\\24098469-s1-p1-2-3-5-9.json", "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\body-presentation-receipts\\24098469-s2-p3-7-9.json" ] }, { "pmid": "37759877", "doi": "10.3390/brainsci13091276", "source_type": "primary study report", "study_group": "PMID37759877", "access_depth": "full_text_partial", "consensus_aspect": "Consensus gap text says simultaneous pre/post brain spectroscopy and cognition in restedomnivores is absent.", "result_comparison": "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_source": "https://pubmed.ncbi.nlm.nih.gov/37759877/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\examinations\\original-6-13-12000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\body-presentation-receipts\\37759877-s1-p0-5-8.json", "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\body-presentation-receipts\\37759877-s2-p0-1.json" ] }, { "pmid": "14561278", "doi": "10.1098/rspb.2003.2492", "source_type": "primary study report", "study_group": "PMID14561278", "access_depth": "abstract_metadata", "consensus_aspect": "Consensus correctly describes 45 youngvegetarians,5g/day six weeks and positiveworkingmemory/Raven scores, withnoMRSintr ial.", "result_comparison": "Originalabstract confirms the population/exposure/positive cognitive findings. Largeeffects remain a real result, but no samepersonbrainmeasurement establishes energeticmediation and subsequentlargertrial narrows expected magnitude.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/14561278/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\examinations\\original-25-32-12000.json" ], "body_receipts": [] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_traffic_first_five_2026-10-12\\creatine-cognition\\consensus-browser-2026-10-12.json", "sha256": "ce5ac9fba49655f1009c9236edd0f942ea1023551cbcd8546fba33b9625d91c8" } ], "independent_blinded_audit": false, "cutoff": "2026-10-12", "completed_utc": "2026-10-13T06:24:57.495602+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }