Creatine

• Muscle preservation
• Cognitive function
• Energy metabolism

• Increased muscle strength and power
• Enhanced exercise performance
• Improved recovery
• Neuroprotection
• Bone health support
• Glucose metabolism

Creatine exerts its physiological effects through multiple mechanisms centered on energy metabolism and cellular protection. The primary mechanism involves the creatine kinase (CK) system, which plays a crucial role in cellular energy homeostasis. Creatine supplementation increases the body’s creatine and phosphocreatine (PCr) stores, particularly in skeletal muscle, brain, and other tissues with high energy demands. In the CK reaction, PCr serves as a rapid energy reserve by donating its phosphate group to ADP to regenerate ATP during periods of high energy demand, such as intense exercise or metabolic stress.

This ATP-PCr system provides an immediate energy source during the first few seconds of high-intensity activity before glycolytic and oxidative energy systems fully activate. Beyond its role in energy metabolism, creatine functions as a cellular pH buffer, helping to delay fatigue by attenuating the accumulation of hydrogen ions during high-intensity exercise. Creatine supplementation also enhances satellite cell proliferation and differentiation, promoting muscle protein synthesis and hypertrophy. This effect is mediated through various signaling pathways, including the activation of mammalian target of rapamycin (mTOR), a key regulator of protein synthesis.

Additionally, creatine increases cellular hydration by drawing water into muscle cells, creating an osmotic gradient that may stimulate protein synthesis and inhibit protein breakdown. In the brain, creatine supports energy metabolism in neurons and acts as a neuroprotective agent by stabilizing mitochondrial membranes, reducing oxidative stress, and inhibiting the opening of the mitochondrial permeability transition pore, thereby preventing apoptosis. Creatine also exhibits antioxidant properties by directly scavenging free radicals and reducing the production of reactive oxygen species. Furthermore, creatine enhances glucose tolerance by increasing the expression of glucose transporter type 4 (GLUT4) and activating AMP-activated protein kinase (AMPK), improving insulin sensitivity and glucose uptake in skeletal muscle.

In bone tissue, creatine promotes osteoblast differentiation and activity while potentially inhibiting osteoclast-mediated bone resorption, contributing to improved bone mineral density. The multifaceted mechanisms of creatine explain its diverse applications beyond sports performance, including potential therapeutic roles in neurodegenerative diseases, muscular dystrophies, sarcopenia, diabetes, and other conditions characterized by impaired energy metabolism or increased oxidative stress.

Creatine supplementation typically follows one of two protocols: a loading phase followed by a maintenance phase, or a consistent daily dose approach. The loading protocol involves consuming 20-25 g/day (or approximately 0.3 g/kg of body weight/day) divided into 4-5 equal doses for 5-7 days, followed by a maintenance dose of 3-5 g/day (or approximately 0.03-0.05 g/kg of body weight/day). This approach rapidly saturates muscle creatine stores and maintains them over time. Alternatively, consuming 3-5 g/day consistently without a loading phase will gradually increase muscle creatine stores over approximately 3-4 weeks, eventually reaching similar levels as the loading protocol.

Both approaches are effective, with the loading protocol providing faster results and the consistent dose approach potentially causing fewer side effects such as gastrointestinal discomfort. Timing of creatine intake is flexible, as research has not consistently demonstrated superior benefits for specific timing protocols (e.g., pre- vs. post-workout). However, consuming creatine with carbohydrates and/or protein may enhance uptake due to insulin’s effect on creatine transport.

Creatine monohydrate, the most common and well-researched form of creatine, demonstrates approximately 99% bioavailability when consumed orally. After ingestion, creatine is absorbed intact through the intestinal epithelium via specific sodium-dependent transporters. Peak plasma concentrations typically occur within 1-2 hours after consumption. The absorption efficiency can vary between individuals due to factors such as intestinal creatine transporter expression, dietary habits, and overall health status.

Once in circulation, creatine is actively transported into tissues, primarily skeletal muscle (which stores approximately 95% of the body’s total creatine), brain, and heart, via the creatine transporter (CreaT). This transport is sodium-dependent and can be influenced by insulin, which enhances creatine uptake into muscle cells. The rate of tissue uptake is a limiting factor in creatine supplementation, which explains why muscle creatine stores increase gradually over several days or weeks, depending on the supplementation protocol. Baseline creatine levels also affect uptake efficiency, with individuals having lower initial levels (such as vegetarians or vegans) typically experiencing greater relative increases in muscle creatine content following supplementation.

Consuming creatine with carbohydrates (approximately 50-100g) increases insulin release, which enhances creatine transport into muscle cells, Co-ingestion with protein (approximately 50g) may provide similar insulin-mediated benefits as carbohydrates, Consuming creatine after exercise may potentially improve uptake due to increased blood flow to muscles and upregulation of creatine transporters, Dividing the daily dose into smaller portions (particularly during loading phases) may improve overall absorption by preventing saturation of intestinal transporters, Maintaining adequate hydration supports optimal creatine transport and retention in tissues, Consuming creatine consistently over time ensures sustained tissue saturation, Alpha-lipoic acid co-supplementation has shown some evidence for enhancing creatine uptake in research settings, Cinnamon extract may potentially enhance creatine transport through insulin-mimetic effects, though more research is needed

The timing of creatine supplementation appears to be flexible, with research showing similar benefits whether consumed before, during, or after exercise, or at other times throughout the day. Some evidence suggests that post-exercise consumption may be marginally beneficial due to increased blood flow to muscles and potential upregulation of creatine transporters, but these effects are likely small compared to the importance of consistent daily intake. For individuals following a loading protocol (20-25g/day for 5-7 days), dividing the daily amount into 4-5 smaller doses (approximately 5g each) spread throughout the day may improve absorption and reduce potential gastrointestinal discomfort. During the maintenance phase (3-5g/day), a single daily dose is typically sufficient and can be taken at any consistent time.

Consuming creatine with meals, particularly those containing carbohydrates and/or protein, may enhance uptake through insulin-mediated mechanisms. For cognitive benefits, some research suggests that morning supplementation may be advantageous, though consistent daily intake appears to be the most critical factor regardless of specific timing. Individuals should establish a consistent supplementation routine that fits their schedule to ensure compliance, as the cumulative effect of regular intake is more important than precise timing for most applications.

• Water retention (primarily intracellular, typically during loading phase)
• Gastrointestinal discomfort (bloating, cramping, diarrhea – more common with loading protocols)
• Weight gain (primarily due to increased water retention and lean mass)
• Potential for dehydration if fluid intake is not increased appropriately
• Muscle cramping (rare and typically related to inadequate hydration)
• Transient increases in creatinine levels (not indicative of kidney damage but may affect interpretation of kidney function tests)

• Pre-existing kidney disease (use with caution and medical supervision)
• Disorders of creatine metabolism (e.g., guanidinoacetate methyltransferase deficiency)
• Medications that affect kidney function (use with caution and medical supervision)
• Pregnancy and lactation (insufficient safety data, though no adverse effects have been reported)
• Polycystic kidney disease (theoretical concern, limited research)

• Nephrotoxic medications (e.g., NSAIDs, certain antibiotics) – theoretical concern for additive stress on kidneys
• Caffeine (some evidence suggests potential interference with creatine’s ergogenic effects, though research is mixed)
• Diuretics (may increase risk of dehydration)
• Probenecid (may affect creatine excretion)
• Cimetidine (potential interaction with creatine transport)

No established upper limit has been determined by regulatory authorities. Most research has used loading doses of 20-25 g/day for 5-7 days followed by maintenance doses of 3-5 g/day, with no significant adverse effects reported. Some studies have used higher maintenance doses (up to 10 g/day) for extended periods without serious adverse effects. The safety of very high doses (>25 g/day) for prolonged periods has not been well-established.

Long-term studies (up to 5 years) using standard protocols have not demonstrated adverse effects on kidney or liver function in healthy individuals. As with any supplement, the principle of using the minimum effective dose is recommended.

In the United States, creatine is regulated as a dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As such, it is not subject to the same pre-market approval process as pharmaceutical drugs. The FDA considers creatine to be Generally Recognized as Safe (GRAS) when used as directed. Manufacturers are permitted to market creatine without demonstrating safety or efficacy to the FDA, though they are responsible for ensuring their products are safe and properly labeled.

The FDA has not approved creatine for the treatment of any medical condition, and manufacturers are prohibited from making specific disease claims (such as ‘treats muscular dystrophy’ or ‘prevents Parkinson’s disease’). However, structure/function claims (such as ‘supports muscle strength’ or ‘enhances athletic performance’) are permitted when accompanied by the standard disclaimer that the statements have not been evaluated by the FDA and that the product is not intended to diagnose, treat, cure, or prevent any disease. The FDA has not established a recommended daily intake or upper limit for creatine consumption. The FDA has taken action against companies marketing creatine with drug claims or unsubstantiated health claims, but has not raised significant safety concerns about creatine itself when used as directed.

Eu: In the European Union, creatine is regulated as a food supplement under Regulation (EC) No 1925/2006 and Directive 2002/46/EC. The European Food Safety Authority (EFSA) has evaluated creatine and approved a health claim related to creatine and increased physical performance during short-term, high-intensity, repeated exercise bouts. This claim can be used for products providing at least 3g of creatine per day. EFSA has also concluded that creatine supplementation at up to 3g per day is safe for the general population. Higher doses up to 5g per day are considered safe for adult athletes.

Canada: Health Canada regulates creatine as a Natural Health Product (NHP). It has been issued a Natural Product Number (NPN) and is approved for use in enhancing athletic performance and increasing muscle strength when used in conjunction with resistance training. Products containing creatine must meet specific quality, safety, and efficacy requirements to be legally sold in Canada. Health Canada has established a recommended dose of 3-5g per day for adults.

Australia: The Therapeutic Goods Administration (TGA) in Australia regulates creatine as a listed complementary medicine. It is included in the Australian Register of Therapeutic Goods (ARTG) and can be sold as a sports supplement. The TGA considers creatine to be generally safe when used as directed, though products making therapeutic claims must be registered with the TGA.

Uk: Post-Brexit, the UK continues to follow regulations similar to the EU approach. Creatine is permitted as a food supplement, with similar restrictions on health claims as in the EU. The UK Food Standards Agency (FSA) has not raised specific concerns about creatine supplementation when used as directed.

Japan: In Japan, creatine is regulated as a food ingredient and is permitted in Foods with Health Claims under the Foods for Specified Health Uses (FOSHU) system. It is generally recognized as safe when used as directed.

Low

$0.10-$0.30 per day for creatine monohydrate powder; $0.30-$0.75 per day for capsules/tablets; $0.50-$2.00 per day for specialized forms (hydrochloride, buffered, etc.)

Creatine monohydrate offers exceptional value for its cost, particularly when purchased as a powder. A typical 500g container of creatine monohydrate powder costs between $15-$30, providing approximately 100-166 daily doses (at 3-5g per day), resulting in a cost of approximately $0.10-$0.30 per day. This makes it one of the most cost-effective evidence-based supplements available. Creatine in capsule or tablet form is more convenient but significantly more expensive on a per-dose basis, typically costing $15-$25 for a 30-day supply, or approximately $0.50-$0.83 per day.

Alternative forms of creatine (hydrochloride, ethyl ester, buffered, etc.) command premium prices, often 2-5 times higher than monohydrate, despite limited evidence for superior efficacy. These specialized forms typically cost $25-$60 for a 30-day supply, or approximately $0.83-$2.00 per day. The cost-effectiveness of creatine is particularly notable when compared to other performance-enhancing supplements. Many pre-workout formulas, protein supplements, and specialized ergogenic aids cost significantly more per serving while offering less robust scientific support.

For athletic performance enhancement, the return on investment is substantial. A meta-analysis by Lanhers et al. (2017) found that creatine supplementation increased maximal strength by an average of 8%, representing significant performance gains for minimal financial investment. For health applications, such as supporting muscle mass in aging populations, creatine’s cost-effectiveness is equally impressive.

The potential healthcare savings from preventing falls and maintaining functional independence through improved muscle strength and bone density far outweigh the minimal cost of supplementation. To maximize cost-efficiency, consumers should consider: 1) Purchasing creatine monohydrate powder in bulk quantities (500g-1kg), which typically offers the lowest cost per gram; 2) Avoiding proprietary blends or specialized forms unless specific digestive issues prevent tolerance of monohydrate; 3) Utilizing subscription services offered by many supplement companies, which typically provide 10-15% discounts; 4) Focusing on reputable brands with third-party testing rather than the absolute cheapest options, as quality assurance is worth the marginal cost difference.

Creatine monohydrate in its dry, powdered form is remarkably stable when stored properly, with a typical shelf life of 2-3 years from the date of manufacture. However, the actual stability can vary based on storage conditions, packaging quality, and exposure to degradation factors. Creatine in capsule or tablet form generally maintains stability similar to powder forms when stored properly. Liquid creatine preparations or pre-mixed solutions have significantly reduced stability, with creatine converting to creatinine (its breakdown product) at a rate of approximately 2-3% per day in neutral pH solutions and even faster in acidic conditions.

This degradation accelerates at higher temperatures, making most liquid creatine products impractical for long-term storage unless specifically formulated with stabilizers or buffering agents. Manufacturers’ expiration dates should be considered the primary guide for shelf life, though properly stored creatine powder may maintain potency beyond this date.

Store creatine in a cool, dry place away from direct sunlight, heat sources, and moisture. Room temperature storage (below 77°F/25°C) is generally adequate, though refrigeration may extend shelf life in hot and humid climates. Keep containers tightly closed to prevent moisture absorption, which can accelerate degradation to creatinine. The original container with desiccant packets is typically optimal for storage.

For powder forms, transfer to an airtight container if the original packaging doesn’t reseal effectively. Avoid storing in bathroom medicine cabinets or kitchen areas where temperature and humidity fluctuations are common. Pre-mixed creatine solutions should be consumed within 24 hours of preparation to minimize conversion to creatinine, particularly if mixed with acidic beverages. If refrigerating, ensure the container is sealed to prevent condensation upon removal.

For travel or portable use, consider using capsule forms or transferring only the amount needed to smaller containers to minimize exposure of the main supply to environmental fluctuations.

Moisture (primary degradation factor, causing hydrolysis to creatinine), Heat (accelerates conversion to creatinine, with significant degradation occurring above 40°C/104°F), Acidic environments (dramatically increase conversion to creatinine; pH below 7 should be avoided for storage), Extended storage in liquid form (particularly problematic in acidic solutions), Exposure to direct sunlight or UV light (can accelerate degradation), Repeated opening of containers (increases exposure to moisture and air), Microbial contamination (more likely in humid environments or with poor handling practices), Freeze-thaw cycles (can affect product integrity, particularly for pre-mixed solutions)

Synthesis Methods

Natural Sources

Quality Considerations

Creatine has a relatively recent history as a nutritional supplement compared to many traditional herbal remedies, with its emergence primarily driven by scientific discovery rather than traditional medicine systems. The compound itself was first identified in 1832 by French scientist Michel Eugène Chevreul, who discovered a new organic constituent in meat extracts, naming it ‘creatine’ after the Greek word ‘kreas’ meaning flesh. In 1847, German scientist Justus von Liebig confirmed that creatine was a regular constituent of animal flesh and found that wild foxes, which are highly active, had 10 times more creatine than captive foxes, establishing the first link between creatine and physical activity. The first documented use of creatine as a performance-enhancing substance occurred in the early 20th century.

Reports suggest that Soviet and Eastern Bloc athletes may have used creatine supplementation as early as the 1960s, though documentation is limited. The scientific understanding of creatine’s role in energy metabolism developed significantly in the mid-20th century. In 1927, phosphocreatine (PCr) was discovered by Philip Eggleton and Grace Palmer Eggleton, and its role in muscle contraction was elucidated in the following decades. The pivotal moment for creatine as a supplement came in 1992 when researchers at the University of Nottingham, led by Roger Harris, published a landmark study in Clinical Science demonstrating that oral creatine supplementation could significantly increase muscle creatine stores.

This study laid the groundwork for the explosion of creatine research and supplementation that followed. The 1992 Barcelona Olympics marked a significant milestone in creatine’s public profile, with reports that many medal-winning British athletes had used creatine supplementation as part of their training regimen. By the mid-1990s, creatine had become widely available as a commercial supplement, with usage spreading rapidly among athletes, bodybuilders, and fitness enthusiasts. The late 1990s and early 2000s saw an exponential increase in scientific research on creatine, expanding beyond athletic performance to explore potential therapeutic applications in various medical conditions.

This period also saw the development of alternative forms of creatine beyond the original monohydrate, though most have shown no significant advantages over the monohydrate form. In the 21st century, creatine research has expanded into areas such as cognitive function, neuroprotection, aging, and various clinical applications, establishing it as one of the most thoroughly researched dietary supplements. Today, creatine is recognized not only as an effective ergogenic aid but also as a potential therapeutic agent for conditions ranging from sarcopenia and osteoporosis to neurodegenerative diseases and traumatic brain injury. Its safety profile has been well-established through decades of research, making it one of the few supplements consistently recommended by sports nutrition experts and increasingly by medical professionals for specific populations.

Lanhers C, Pereira B, Naughton G, Trousselard M, Lesage FX, Dutheil F. Creatine Supplementation and Upper Limb Strength Performance: A Systematic Review and Meta-Analysis. Sports Med. 2017;47(1):163-173., Chilibeck PD, Kaviani M, Candow DG, Zello GA. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis. Open Access J Sports Med. 2017;8:213-226., Devries MC, Phillips SM. Creatine supplementation during resistance training in older adults-a meta-analysis. Med Sci Sports Exerc. 2014;46(6):1194-1203., McMorris T, Mielcarz G, Harris RC, Swain JP, Howard A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007;14(5):517-528., Forbes SC, Candow DG, Ostojic SM, Roberts MD, Chilibeck PD. Meta-Analysis Examining the Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults. Nutrients. 2021;13(6):1912.

Creatine supplementation for cognitive enhancement in Parkinson’s disease, Effects of creatine supplementation on cognitive function in healthy aging, Creatine supplementation for muscle preservation during cancer treatment, Creatine and resistance training for sarcopenia prevention in older adults, Creatine supplementation for traumatic brain injury recovery, Creatine effects on depression and mood disorders