Creatine monophosphate – 14 Interesting Facts, Indications, Side effects, Drug Interactions & Contraindications

Creatine monophosphate – Interesting Facts

1. Creatine monophosphate is a dietary supplement similar to the natural compound creatine phosphate, which is an essential component of the energy-building system in muscle cells.
2. Phosphocreatine is a nitrogen-containing compound found naturally in meats and fish. Creatine is also synthesized endogenously by the kidney, liver, and pancreas from arginine, glycine, and methionine. Normal dietary needs of creatine are suggested to be approximately 2 g/day to replace catabolized creatine.
3. Many sports nutrition experts believe that the majority of world-class athletes use creatine.
4. It is also widely used at the collegiate level. Quality scientific studies have been conducted to evaluate the exercise response to creatine loading in various forms of sport (e.g., jump squats, sprinting, weight lifting), and in many of these studies, creatine exhibited ergogenic properties.
5. The most beneficial effects of creatine appear to be seen in events requiring extremely high-intensity effort for very brief periods (e.g., less than 60 seconds). High intensity exercise increases the demands on the anaerobic energy system and creatine loading helps supplement this.
6. Overall, creatine supplementation along with resistance exercise may enhance exercise performance and increase lean body mass.
7. Creatine supplementation is not considered doping and is not banned by NCAA or USOC.
8. Creatine has been available over-the-counter (OTC) as a dietary supplement since 1993; it is currently not classified as a drug by the FDA.
9. However, in March 2002, the FDA granted orphan drug status to The Avicena Group for creatine in patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease).
10. The Avicena Group (www.avicenagroup.com) has been studying creatine (Neotine®) for use in ALS patients. Safety and efficacy has been demonstrated in these patients.
11. Creatine appears to slow progression of ALS and improve patients’ quality of life. Neotine® is currently in Phase III trials for this indication.
12. A new formulation of creatine, PD-02, has been developed by Avicena for evaluation in the treatment of Parkinson’s disease.
13. A large scale Phase III trial is currently underway through the NIH National Institute of Neurological Disorders and Stroke (NINDS) to assess the efficacy of creatine in slowing progression of the disease.
14. A previously completed Phase II futility clinical trial showed potential benefit of the drug.

Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?

In summary, because creatine has a completely different chemical structure, it is not an anabolic steroid.

Does creatine cause kidney damage/renal dysfunction?

• Questions and concerns involving creatine supplementation and kidney damage/renal dysfunction are common.
• In terms of pervasive misinformation in the sport nutrition arena, the notion that creatine supplementation leads to kidney damage/renal dysfunction is perhaps second only to the myth that protein supplementation and high habitual protein intake causes kidney damage.
• Today, after > 20 years of research which demonstrates no adverse effects from recommended dosages of creatine supplements on kidney health, unfortunately, this concern persists.
• While the origin is unknown, the connection between creatine supplementation and kidney damage/renal dysfunction could be traced back to two things: a poor understanding of creatine and creatinine metabolism and a case study published in 1998.

Does creatine cause hair loss / baldness?

• The vast majority of speculation regarding the relationship between creatine supplementation and hair loss/baldness stems from a single study by van der Merwe et al. where college-aged male rugby players who supplemented with creatine (25 g/day for 7 days, followed by 5 g/day thereafter for an additional 14 days) experienced an increase in serum dihydrotestosterone (DHT) concentrations over time.
• Specifically, DHT increased by 56% after the seven-day loading period, and remained 40% above baseline values after the 14-day maintenance period.
• These results were statistically significant compared to when the subjects consumed a placebo (50 g of glucose per day for 7 days, followed by 30 g/day for 14 days thereafter).
• Given that changes in these hormones, particularly DHT, have been linked to some (but not all) occurrences of hair loss/baldness, the theory that creatine supplementation leads to hair loss / baldness gained some momentum and this potential link continues to be a common question / myth today.
• It is important to note that the results of van der Merwe et al. have not been replicated, and that intense resistance exercise itself can cause increases in these androgenic hormones.

Does creatine lead to dehydration and muscle cramping?

• Speculation exists that creatine supplementation causes dehydration and muscle cramping [72, 73]. In the early 2000’s, with limited data and based primarily on speculation, the American College of Sports Medicine (ACSM) recommended that individuals controlling their weight and exercising intensely or in hot environments should avoid the use of creatine supplementation [74].
• The physiological rationale suggesting that creatine supplementation may cause dehydration and muscle cramping is based on the premise that creatine is an osmotically active substance found primarily in skeletal muscle and may alter whole-body fluid distribution by preferentially increasing intracellular water uptake and retention, particularly over the short-term [38, 75].
• In situations of body water loss, such as severe sweating from exercise and/or increased environmental temperature, the bound intracellular fluid, in theory, may be detrimental to thermal regulation and lead to extracellular dehydration, electrolyte imbalance and muscle cramping or other heat-related musculoskeletal issues [44]. 

Does creatine increase fat mass?

A common misconception among exercise enthusiasts is that creatine supplementation leads to increased fat mass, possibly stemming from the observed increase in overall body mass following creatine use. However, extensive randomized controlled trials, spanning from one week to two years, have consistently disproven this belief. Short-term creatine supplementation (7 days) demonstrated no impact on fat mass in both young and elderly participants, though an increase in fat-free mass was noted [86, 87].

Similarly, swimmers showed no body composition changes after three weeks of creatine supplementation [88]. When combined with high-intensity interval training, creatine supplementation showed no effect on body composition in female recreational athletes [89]. Studies examining creatine’s impact during resistance training overreaching also found no changes in fat mass [70].

Research on recreational male bodybuilders consuming 5 g/day of creatine, whether taken before or after training, showed no alterations in fat mass [90]. Extended studies lasting 6-8 weeks further support these findings. Becque et al. [91] reported no fat mass changes following six weeks of supplementation combined with resistance training. Another six-week study found no significant variations in fat mass or body fat percentage with creatine supplementation [42].

Additionally, an eight-week study during a rugby union football season confirmed no impact of creatine supplementation on fat mass [92]..

While some may argue that studies lasting eight weeks or less are inadequate to definitively determine creatine’s impact on fat mass, numerous investigations have employed substantially longer intervention periods. In one notable study, healthy resistance-trained males participated in a double-blind trial, receiving either creatine supplementation (20 g/day for the first week, followed by 5 g/day for 11 weeks) or a placebo [^93].

The results showed increases in lean body mass and muscle fiber size, while body fat percentage and fat mass remained unchanged throughout the 12-week training period [^93].

Another study focusing on elderly males (approximately 70 years old) demonstrated that 12 weeks of creatine supplementation during resistance training produced no significant changes in fat mass compared to placebo [^94].

Similarly, Gualano et al. investigated creatine supplementation effects over 24 weeks in older females, both with and without resistance training, finding no impact on fat mass [^95]. A 32-week investigation by Candow et al. [^96] studied older adults (aged 50-71 years) who were randomly assigned to take creatine or placebo either before or after resistance training (three times weekly).

While participants experienced increased lean tissue and strength over time, along with decreased fat mass, these changes were not attributed to creatine supplementation. From a medical standpoint, pediatric patients with acute lymphoblastic leukemia who received creatine supplementation (0.1 g/kg/day) for two consecutive 16-week periods showed significant fat mass reduction, whereas those not taking creatine experienced fat mass gains [^97].

Two comprehensive studies by Lobo et al. [^98] examining postmenopausal women found that low-dose creatine supplementation over one year did not affect absolute or relative body fat measurements. Moreover, even extended creatine supplementation lasting two years showed no significant impact on fat mass in this population [^99].

A recent systematic review and meta-analysis by Forbes and colleagues 100 examined randomized controlled trials investigating the combined effects of creatine supplementation and resistance training on fat mass in adults aged 50 and above.

The analysis encompassed nineteen studies with 609 total participants. The findings revealed that subjects taking creatine experienced a more substantial decrease in body fat percentage.

While absolute fat mass reduction showed no statistically significant difference between groups, the creatine-supplemented participants lost approximately 0.5 kg more fat mass than those taking placebo.

In summary, creatine supplementation does not increase fat mass across a variety of populations.

Indications

• Amyotrophic lateral sclerosis (ALS)
• Ergogenesis
• Parkinson’s disease

To achieve ergogenesis† by enhancing anaerobic metabolism during strenuous, short-term exercise

NOTE: The concept of a ‘loading dose’ followed by a ‘maintenance dose’ is generally employed in dosing creatine.

Mechanism of Action

• Creatine acts as an “energy buffer”. Adenosine triphosphate is the free energy source used to drive many biological processes including muscle contractions. Adenosine triphosphate provides energy through hydrolysis of its high-energy phosphoanhydride bonds.
• During high intensity exercise, muscle stores of ATP are depleted in approximately 10 seconds. Therefore, ATP must be continuosly regenerated.
• The ability to replenish ATP in muscle is directly related to the amount of creatine which is present in muscle as either free creatine or phosphocreatine. Free creatine can undergo rapid phosphorylation to form phosphocreatine.
• Resynthesis of ATP is catalyzed by creatine kinase which transfers the phosphate group from phosphocreatine to adenosine diphosphate (ADP) to form ATP. Creatine supplementation acts to raise muscle stores of creatine phosphate thereby increasing the amount of ATP available during intense physical activity.

Pharmacokinetics

Creatine monohydrate is administered orally. Creatine is rapidly absorbed with peak plasma concentrations occurring in approximately 1 hour.

Creatine is primarily distributed into skeletal muscle. Animal data suggest that creatine distribution into muscle is a saturable process, however, no equivalent data are available for humans.

A 70 kg male has approximately 120 g of creatine, 95% of which is in skeletal muscle. Of the total creatine in muscle, 60% exists as phosphocreatine and the remainder as free creatine.

Creatine is metabolized to creatinine, however, the exact steps involved have not been determined. Excretion is via the urine as both creatine and creatinine.

•Route-Specific Pharmacokinetics

Oral Route

Following creatine supplementation, both total creatine (TCr) and phosphocreatine (PCr) are increased with the greatest increases occurring the first 2 days of supplementation. Persons with low initial creatine concentrations (e.g., vegetarians) tend to have the greatest increases in TCr.

Coadministration of creatine with a simple carbohydrate such as glucose may increase TCr and PCr to a greater extent than with creatine alone, possibly through an insulin-mediated mechanism.

Single oral doses of 5 g may produce peak creatine plasma concentrations of 690—1000 micro mol/L.

Safety Profile and Regulatory Status

Recent research reinforces creatine monohydrate’s exceptional safety record. An April 2025 comprehensive review by leading creatine researchers documented over 680 peer-reviewed clinical trials involving more than 12,800 participants who received creatine supplements at dosages up to 30 grams per day for 14 years across all age groups—from infants to elderly individuals—with no reported clinical adverse events. Analysis of over 28.4 million adverse event reports across the United States, Canada, Australia, and Europe revealed that creatine was mentioned in only approximately 0.0007% of reports despite billions of doses consumed worldwide over the past 30 years.

Creatine monohydrate remains the only form of creatine with substantial evidence supporting bioavailability, efficacy, and safety. It continues to be the form explicitly recommended by professional organizations and approved for use globally as a dietary ingredient and food additive.

Cognitive and Neurological Applications

One of the most promising recent developments involves creatine’s potential role in cognitive disorders. A 2025 pilot study at the University of Kansas Medical Center examined creatine monohydrate supplementation in Alzheimer’s disease patients—the first clinical trial of its kind. The study demonstrated that 20 grams daily for 8 weeks increased brain total creatine by 11% and produced improvements in global cognition, fluid cognition, list sorting, oral reading, and executive function tests. All 19 of 20 participants achieved at least 80% compliance with the intervention, supporting its feasibility in this population.

Side Effects

1. anxiety
2. atrial fibrillation
3. constipation
4. dehydration
5. depression
6. diarrhea
7. dizziness
8. dyspnea
9. fatigue
10. fluid retention
11. headache
12. hypercholesterolemia
13. muscle cramps
14. myopathy
15. nausea
16. rash
17. seizures
18. tremor
19. vomiting
20. weight gain
21. xerostomia

Monitoring Parameters

• laboratory monitoring not necessary

Contraindications

Creatine monophosphate, like other creatine supplements, is generally well tolerated in healthy individuals; however, certain conditions warrant avoidance or caution.

Absolute Contraindications

• Known hypersensitivity or allergy to creatine or any formulation components.
• Diabetes mellitus.
• Nephrotic syndrome or significant renal impairment.
• Pregnancy.
• Breastfeeding.

Aging, Muscle Health, and Sarcopenia

For older adults, creatine supplementation combined with resistance training demonstrates measurable benefits for combating sarcopenia—age-related muscle loss affecting approximately 200 million people globally age 65 and older. Current research from 2025 shows that creatine monohydrate supplementation enhances lean body mass, muscle strength, and functional capacity in aging populations.​

A particularly significant finding involves bone health. When combined with resistance training (0.1 grams/kg on training days, 3 days weekly for 10 weeks), creatine reduced urinary markers of bone resorption by 27% compared to a 13% increase in placebo groups. This suggests creatine activates osteoblasts (bone-forming cells), potentially protecting against osteoporosis-related fractures in aging adults.​

Research also indicates that 2 years of creatine supplementation (0.14 grams/kg/day) combined with resistance training and walking improved walking speed by approximately 0.1 m/s over 80 meters in postmenopausal women—a clinically meaningful improvement for fall prevention.

Sources

1. Antonio J, Candow DG, Forbes SC, Gualano B, Jagim AR, Kreider RB, Rawson ES, Smith-Ryan AE, VanDusseldorp TA, Willoughby DS, Ziegenfuss TN. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? J Int Soc Sports Nutr. 2021 Feb 8;18(1):13. doi: 10.1186/s12970-021-00412-w. PMID: 33557850; PMCID: PMC7871530.https://pmc.ncbi.nlm.nih.gov/articles/PMC7871530/