Creatine Monohydrate under the microscope: mechanism, benefits and clinical evidence.

Introduction

Creatine monohydrate has been unfairly oversimplified: it's associated with big muscles and packed gyms, when in reality it's one of the most powerful and versatile bioenergetic molecules in the human body. Behind every rep, sprint, or quick thought, there's an invisible system recycling energy at near-instantaneous speed: the phosphocreatine system. Understanding how this compound works—from its intestinal absorption to its role in regenerating muscle and brain ATP—is to understand the physiological basis of human performance.

Today, creatine is not just a supplement for athletes: it's a tool for longevity, neuroprotection, and metabolic efficiency. Its strategic use can improve both cognition and body composition, with a scientific basis so solid that few nutritional compounds can match it.

1. Physiological Mechanism of Creatine (Absorption, Metabolism and Cellular Storage)

Creatine monohydrate powder is almost completely absorbed (≈99%) in the intestine, quickly entering the bloodstream Less than 1% of the dose is degraded to creatinine during digestive transit, as creatine is quite stable at body pH levels during digestion. Once in circulation, creatine is actively transported into tissues – primarily skeletal muscle (which stores ~95% of the body's creatine) – via a specific sodium-chloride cotransporter known as the creatine transporter ( SLC6A8 gene). Since this transport involves the movement of sodium, intracellular water enters along with creatine to maintain osmolarity, causing some intracellular water retention and an increase in the volume of muscle cells. .

Within the muscle fiber, free creatine is rapidly phosphorylated by the enzyme creatine kinase (CK) to form phosphocreatine (PCr) , a high-energy compound that serves as an immediate reservoir of phosphates to regenerate ATP from ADP during intense, short-duration efforts. Approximately 40% of intramuscular creatine remains in free form and ~60% in the form of phosphocreatine. This creatine-PCr system allows chemical energy to be stored in the muscle and released quickly when extra ATP is demanded during extreme physical activity. Each day, a portion of the creatine pool (approximately 1–2 grams) is spontaneously broken down into creatinine, which is excreted by the kidneys. Therefore, the body requires a daily supply (either through endogenous synthesis from amino acids, ingestion of foods such as meat, or supplements) to maintain its stores. A typical omnivorous diet provides approximately 1–2 g/day of creatine, which maintains muscle stores at approximately 60–80% of their total saturation. Creatine supplementation allows for muscle supersaturation and raises creatine/PCR concentrations ~20–40% above baseline levels. thus increasing the energy potential available in short bursts of high intensity.

2. Effects on the Health of the General Population

In individuals from the general population (beyond the sports field), supplementation with creatine monohydrate has shown multiple beneficial effects supported by scientific evidence:

• Cognitive function: Several studies suggest improvements in cognitive performance with creatine, especially in memory and attention tasks in older adults. For example, five out of six studies with healthy older adults showed higher cognitive scores (memory, mental speed) in those who received creatine compared to controls. These findings link creatine to a possible neuroprotective or brain energy-supporting effect, given that the brain also uses creatine to recycle ATP in neurons.

• Aging and sarcopenia: Creatine may mitigate some effects of aging. Its long-term use, in combination with exercise, has been documented to help preserve muscle mass and function in older adults, combating sarcopenia (muscle loss). Its neuroprotective potential in neurodegenerative diseases and its ability to indirectly improve bone density by enabling greater physical activity in the elderly are also being investigated. These anti-aging effects position creatine as a promising supplement for healthy aging.

• Body composition: In the general active population, creatine promotes body changes toward greater lean mass . Meta-analyses indicate that those who supplement creatine (along with training) gain more fat-free muscle mass and experience slight reductions in body fat percentage, compared to those who do not supplement. Part of the initial weight gain with creatine is due to increased intracellular water in the muscle (which is not equivalent to fat); in the long term, creatine enables more intense workouts that lead to greater actual muscle hypertrophy.

• Metabolic health: There is evidence that creatine improves metabolic parameters, especially when combined with exercise. In people with insulin resistance or type 2 diabetes, supplementation plus exercise was associated with better glycemic control (lower blood glucose and HbA1c) and greater glucose uptake by muscle. Furthermore, creatine may mitigate muscle loss in the context of metabolic syndrome or obesity, supporting overall health. Importantly, clinical studies have not found consistent adverse effects of creatine on kidney or liver function when used at appropriate doses, supporting its safety in healthy populations.

3. Effects on Athletes and Strength/High Intensity Training

For athletes and individuals who engage in strength training or anaerobic activities, creatine monohydrate is one of the most scientifically supported supplements, producing significant improvements in performance and muscle adaptations. Its main ergogenic benefits include:

• Increased anaerobic performance (strength and power): Creatine raises intramuscular phosphocreatine stores, increasing the capacity to rapidly generate ATP during maximal effort. In practice, this translates into higher levels of strength and explosive power, allowing for heavier lifting or faster sprints. Numerous studies show that subjects taking creatine can perform more repetitions at high intensity and with better quality, delaying neuromuscular fatigue in comparisons to placebo. Quantitatively, improvements of 5–15% have been observed in maximal strength and power tests after creatine saturation, depending on the task and protocol studied.

• Increased anaerobic endurance: In addition to peak power, creatine improves the ability to sustain repeated anaerobic efforts . By increasing the pool of available phosphocreatine, the muscle can resynthesize ATP for longer periods during successive bouts of high-intensity exercise before depleting its reserves. This allows, for example, for sprinting a few seconds longer or performing several explosive sets with less performance drop between them. In sprint and interval studies, those supplementing creatine maintained higher power outputs in subsequent efforts compared to those not supplementing, reflecting improved endurance in the anaerobic range.

• Hypertrophy and muscle gain: Creatine facilitates greater muscle mass gains when combined with resistance training. Meta-analyses have found that creatine supplementation amplifies lean mass gains compared to training alone. The mechanisms include increased training volume (allowing for more intense training), increased cellular hydration (which can signal protein synthesis), and improved recovery that allows for the accumulation of more anabolic stimulus. With several weeks of use, a lean body mass increase of approximately 1–2 kg is typically observed in creatine users, in addition to normal training adaptations. Creatine has also been reported to slightly increase the size of type II (fast-twitch) muscle fibers in long-term strength training protocols.

• Improved muscle recovery: Creatine supplementation appears to accelerate recovery after intense exercise . Lower levels of markers of muscle damage and inflammation (e.g., serum creatine kinase, IL-6) have been observed following strenuous sessions in subjects taking creatine compared to placebo. This suggests that creatine helps repair muscle fibers more quickly and replenish energy stores (ATP and phosphocreatine) after exercise. Consequently, athletes can train more frequently or withstand higher loads with a lower risk of overtraining. In short, creatine enhances both acute performance and chronic adaptation to training in high-intensity disciplines.

4. Recommended Dose, Loading/Maintenance Strategies and Optimal Absorption

Dosage and protocols: The typically recommended dose of creatine monohydrate for adults is 3–5 grams daily (maintenance dose) to sustain elevated intramuscular levels once saturation is reached. A common protocol is to start with a 5–7 day loading phase at ~20 g/day (divided into four 5 g doses), followed by a maintenance phase of 3–5 g/day This loading strategy allows for a rapid increase (in about a week) in muscle creatine content of 20–40%. , achieving more immediate ergogenic benefits (although often with ~1–2 kg of initial water weight gain) However, loading is not essential : small daily intakes (3–5 g) also gradually increase muscle stores to maximum in ~3–4 weeks For many recreational users, continuous supplementation without a loading phase is sufficient to achieve results, avoiding sudden weight gain. In individuals with higher lean body mass, slightly higher doses (e.g., 0.1 g/kg/day) may be adequate for maintenance. It is important to note that very high single doses (>10 g) do not improve absorption and may cause gastrointestinal upset (e.g., diarrhea). Therefore, large daily doses should be divided into smaller doses throughout the day.

Optimizing Absorption: Creatine monohydrate is moderately soluble in water (≈14 g/L at 20°C) and is efficiently absorbed intestinally on its own. However, certain dietary cofactors can enhance its transport to muscle. Classic studies have shown that ingesting creatine with a high source of simple carbohydrates leads to greater intramuscular creatine accumulation due to insulin stimulation. Insulin facilitates creatine uptake by myocytes by activating the SLC6A8 transporter, so strategies such as taking creatine post-workout with carbohydrates or a high-carbohydrate/high-protein meal can maximize its muscle retention. For example, co-ingestion of approximately 50–100 g of carbohydrate has been shown to increase muscle creatine compared to taking it with water alone. In practice, many athletes consume it along with their protein and carbohydrate shake after training to optimize both glycogen resynthesis and creatine loading. It should be noted that creatine's solubility in hot liquids is greater, but this does not affect its physiological effectiveness. The key is to ensure consistent daily supplementation. Finally, staying well-hydrated and using quality products guarantees better absorption and minimizes risks. In summary, 3–5 g of creatine monohydrate (pure, powder) daily is a safe and effective dose for most adults. A short, optional loading phase can be used for faster benefits, and the intake should be accompanied by a source of carbohydrates to optimize absorption and muscle anabolism.

5. Technical Glossary

• Phosphocreatine (PCr): a creatine molecule bound to a high-energy phosphate group. Phosphocreatine is stored primarily in muscle (and to a lesser extent in the brain) and functions as an energy buffer , allowing for the near-instantaneous regeneration of ATP during intense muscle contraction. When ATP is consumed and converted to ADP, phosphocreatine donates its phosphate to ADP to resynthesize ATP, sustaining the contraction for a few additional seconds ( anaerobic alactic energy system ). PCr stores are depleted after approximately 10–15 seconds of maximal effort, at which point power output declines. A higher initial concentration of phosphocreatine (e.g., through supplementation) delays fatigue and allows for sustained explosive power.

• Intracellular water retention: a phenomenon by which muscle cells increase their water content as a result of creatine accumulation. Creatine is osmotically active and hygroscopic , meaning it draws water into the cells. In the first few days of high-dose supplementation (loading phase), a rapid weight gain of approximately 1–2 kg is typical, primarily due to increased water volume in the muscle (not to be confused with fat gain). This additional cellular hydration can be beneficial, as a well-hydrated cell promotes anabolic pathways of protein synthesis and reduces muscle breakdown. Creatine-induced water retention occurs mainly intracellularly (within the muscle) and not so much in the extracellular space, so it does not usually cause generalized edema. In the long term, several studies show that creatine does not significantly alter total body water beyond the muscle adaptations achieved. In other words, the "swelling" effect is primarily transient and intracellular. Maintaining adequate fluid and electrolyte intake while taking creatine helps to balance this fluid distribution.

• SLC6A8 (creatine transporter): a membrane protein (also called CreaT or CT1 ) responsible for the active uptake of creatine from the bloodstream into cells, particularly in skeletal muscle and the brain. It belongs to the sodium-chloride-dependent cotransporter (SLC6) family, meaning it moves creatine molecules coupled to the transport of sodium (Na+) and chloride (Cl-) ions down their concentration gradients. This mechanism activates an osmotic draw of water (see intracellular water retention above) and concentrates creatine within the muscle fiber against its concentration gradient. The SLC6A8 gene encodes this transporter protein; mutations that inactivate it cause creatine transporter deficiency syndrome, characterized by very low levels of creatine in the brain and muscles, cognitive impairment, and muscle weakness. In healthy individuals, SLC6A8 activity is regulated by creatine availability (it will become saturated when muscle stores are full) and by the action of insulin, which can increase the translocation of these transporters to the cell membrane, facilitating creatine entry. In short, SLC6A8 is the "gateway" for creatine into cells, essential for the ingested supplement to exert its biological effects.

References (APA Format)

• Antonio, J., Candow, DG, Forbes, SC, Gualano, B., Jagim, AR, Kreider, RB, et al. (2021). Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? Journal of the International Society of Sports Nutrition, 18 (1), Article 13.

• Duran-Trío, L., Fernandes-Pires, G., Simicic, D., Grosse, J., Roux-Petronelli, C., Bruce, SJ, … & Braissant, O. (2021). A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism . Scientific Reports, 11 (1), 1636.

• Gutiérrez-Hellín, J., Del Coso, J., Franco-Andrés, A., Gamonales, JM, Espada, MC, González-García, J., … & Varillas-Delgado, D. (2025). Creatine supplementation beyond athletics: Benefits of different types of creatine for women, vegans, and clinical populations—A narrative review . Nutrients, 17 (1), 95.

• Marshall, S., Kitzan, A., Wright, J., Bocicariu, L., & Nagamatsu, L.S. (2025). Creatine and cognition in aging: A systematic review of evidence in older adults . Nutrition Reviews. Advance online publication. https://doi.org/10.1093/nutrit/nuaf135  .

• Młynarska, E., Leszto, K., Katańska, K., Prusak, A., Wieczorek, A., Jakubowska, P., … & Franczyk, B. (2025). Creatine supplementation combined with exercise in the prevention of type 2 diabetes: Effects on insulin resistance and sarcopenia . Nutrients, 17 (17), 2860.