Creatine
Creatine buffers cellular ATP via creatine phosphate, mainly in muscle and brain. Meat is the main dietary source.
Peat's view
[edit]When a muscle cell contracts, phosphate separates from ATP and is replaced by transfer of phosphate to ADP from creatine phosphate, keeping ATP available during the contraction.[1]
Sleep deprivation
[edit]A single high dose of creatine monohydrate (0.35 g/kg, roughly 25 g for a 70 kg adult) taken before 21 hours of sleep deprivation raised brain phosphocreatine and ATP, prevented the usual drop in brain pH, and improved cognitive performance (logical/numerical tasks, language-processing speed, psychomotor vigilance) compared to placebo over the sleep-deprived night.[2] A follow-up trial found the same protection at a lower single dose (0.2 g/kg, roughly three-quarters of the original amount): during 21 hours of sleep deprivation it still improved logical/numerical tasks, language-processing speed, and psychomotor vigilance versus placebo, up to 12%, though the effect was somewhat smaller than the full 0.35 g/kg dose.[3]
Exercise and central fatigue
[edit]Rising brain serotonin during exercise is one proposed driver of "central fatigue," the loss of motivation, coordination, and drive that shows up before the muscles themselves give out.[4] In 20 untrained men given either 20 g/day creatine monohydrate or placebo for 7 days, blood serotonin rose in both groups immediately after an exhaustive treadmill test, but the rise was smaller and reversed faster in the creatine group.[4] Dopamine ran higher in the creatine group throughout recovery without reaching statistical significance. The trial was small (n=10 per arm) and measured blood rather than brain serotonin directly.
Depression
[edit]Adding creatine monohydrate to an SSRI accelerated and strengthened the antidepressant response in a randomized, placebo-controlled trial of women with major depressive disorder.[5] A 2026 systematic review pooling five randomized trials (238 participants, mostly major depressive and bipolar depression) concluded creatine monohydrate "shows promise" as an SSRI or psychotherapy adjunct, while flagging two cases of hypomania/mania among treated participants and calling the overall evidence base still small.[6] Dietary creatine intake tracks depression risk in the general population too. In a cross-sectional analysis of 22,692 NHANES participants, depression prevalence ran 10.23 per 100 persons in the lowest quartile of dietary creatine intake versus 5.98 per 100 in the highest quartile, an inverse association (adjusted odds ratio 0.68) that held after adjusting for income, BMI, smoking, physical activity, and antidepressant use.[7] No dedicated randomized trial of creatine for anxiety disorders has been published as of 2026.
Cancer immunity
[edit]Creatine uptake powers CD8 T cell activity against tumors. Mice lacking the creatine transporter (CrT/Slc6a8) mounted a severely weakened antitumor T cell response. Supplementing creatine in normal mice significantly suppressed tumor growth across several mouse tumor models, and combining creatine with a PD-1/PD-L1 checkpoint blockade produced a synergistic effect beyond either treatment alone. Creatine acts as a "molecular battery," storing bioenergy that T cells draw on during an immune attack.[8] These results come from mouse tumor models; a randomized trial of creatine supplementation as a human cancer treatment or immunotherapy adjunct has not been published as of 2026.
Lipofuscin and longevity
[edit]In 162 aged mice, oral creatine supplementation raised median healthy lifespan by 9%, improved neurobehavioral test performance, and produced significantly less brain accumulation of lipofuscin (the "aging pigment" from peroxidized PUFA membranes) alongside a trend toward lower reactive oxygen species; gene expression shifted toward neuronal growth, neuroprotection, and learning pathways.[9] Human autopsy work on lipofuscin's origin found the pigment forms from peroxidative destruction of polyunsaturated membranes inside mitochondria themselves, cumulative and irreversible damage most visible as brown atrophy of the heart in relatively young people who died of wasting conditions.[10]
See also
[edit]References
[edit]- ↑ Ray Peat, "Fatigue, Aging, and Recuperation." "When a muscle cell is stimulated enough to cause a contraction... phosphate ions separate from ATP, and are replaced by the transfer of phosphate to ADP from creatine phosphate."
- ↑ Gordji-Nejad A, et al. "Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation," Sci Rep. 2024;14:4937.
- ↑ Gordji-Nejad A, Matusch A, Hengstler L, et al. "Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance," Nutrients. 2026;18(8):1192.
- ↑ 4.0 4.1 Moghadasi M, Rahimi E, Nematollahzadeh Mahani M, Molaee AA. "Effect of creatine supplementation on brain neurotransmitters after an exhaustive aerobic exercise," Braz J Biomotricity. 2012;6(3):213-221.
- ↑ Lyoo IK, et al. "A randomized, double-blind, placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder," Am J Psychiatry. 2012;169(9):937-945.
- ↑ Jeryous Fares B, Zhou C, Fabiano N, et al. "The Effect of Creatine Monohydrate on Mental Disorders: A Systematic Review of Randomized Controlled Trials," Can J Psychiatry. 2026.
- ↑ Bakian AV, Huber RS, Scholl L, Renshaw PF, Kondo D. "Dietary creatine intake and depression risk among U.S. adults," Transl Psychiatry. 2020;10(1):52.
- ↑ Di Biase S, Ma X, Wang X, et al. "Creatine uptake regulates CD8 T cell antitumor immunity," J Exp Med. 2019;216(12):2869-2882. PMID 31628186.
- ↑ Bender A, Beckers J, Schneider I, et al. "Creatine improves health and survival of mice," Neurobiol Aging. 2008;29(9):1404-1411. doi:10.1016/j.neurobiolaging.2007.03.001. PMID 17416441.
- ↑ Koobs DH, Schultz RL, Jutzy RV. "The origin of lipofuscin and possible consequences to the myocardium," Arch Pathol Lab Med. 1978;102(2):66-68. PMID 579966.