New analysis overturns decades of debate, revealing that creatine’s biggest threats aren’t cancer or kidney failure, but misinformation and poor quality supplements.
Study: A brief review of the most common safety concerns about ingesting creatine. Image credit: djavan rodriguez/Shutterstock.com
In a recent review published on Frontiers in Nutritionresearchers evaluated long-standing health concerns about creatine monohydrate, a widely used supplement.
Their findings show that when taken appropriately, creatine appears to be safe. Any side effects are generally mild and most often associated with consuming high single doses. However, further research is needed to understand the risks for those who are pregnant or have kidney disease.
Creatine and Cancer Risk
The debate over creatine’s potential carcinogenicity often centers on heterocyclic amines (HCAs), compounds formed when creatine, amino acids and sugars react at high temperatures during cooking.
Although HCAs can be mutagenic at very high concentrations in laboratory models, the amounts found in cooked meat (and even more so in creatine supplements) are much lower. Human evidence showing direct harm is almost non-existent. In a human trial examining the effect of creatine on HCA formation, only nine urine samples contained measurable HCA, and the majority were from placebo recipients, suggesting that creatine does not increase mutagen production.
Some mechanistic studies raise theoretical concerns that increased creatine availability may support cancer cell energy metabolism or metastasis through creatine kinase-related pathways. Evidence from some mouse models suggests that there are increases in metastatic potential due to Smad2/3.
However, other experiments report exactly the opposite results: creatine and its analog, cyclocreatine, often slow tumor growth, enhance the activity of cytotoxic T lymphocytes (CD8 T-cells), which are crucial for targeting and destroying cancer cells and may even increase the effectiveness of chemotherapy.
These inconsistencies reflect the large variability in cancer types and experimental models. As a result, current evidence does not support claims that creatine increases the risk of cancer in humans. Instead, the primary safety issue lies in the purity of the supplement, as some commercial products may contain contaminants or even unapproved medicinal ingredients if they have not been tested by a third party.
Creatine and renal function
Concerns about kidney damage date back to isolated case reports in the 1990s, many of which involved individuals with pre-existing kidney disease, extreme training loads, or concomitant use of nephrotoxic substances. Some early animal models also suggested possible damage. However, interspecific differences make extrapolation of such findings difficult.
A large body of human research now demonstrates that creatine does not harm kidney function in healthy individuals. Serum creatinine often increases during supplementation, but this increase reflects increased creatine turnover rather than decreased filtration. When more accurate renal markers such as cystatin C, urine proteins, electrolytes, or direct glomerular filtration techniques are used, renal function remains stable. Studies using doses up to 20 grams per day and lasting up to five years have shown no evidence of kidney damage.
Even in higher-risk groups, including adults on dialysis, the elderly with diabetes, people with rheumatic diseases, and even a person with a single kidney, creatine has not caused clinically significant decreases in kidney health when properly monitored. However, because the evidence in people with significant renal impairment is limited, the authors advise close monitoring and the use of creatinine-independent biomarkers if supplementation is considered.
Hydration, thermoregulation and muscle cramps
Creatine is osmotically active and increases intracellular water, especially during loading phases involving high daily doses. This observation led to speculation that creatine may decrease extracellular water, reduce heat dissipation, and contribute to dehydration-related injuries, particularly after anecdotal reports involving athletes training in hot environments.
However, controlled studies have consistently refuted these fears. Research involving intense exercise in heat, dehydration protocols, and high humidity found that creatine did not worsen plasma volume loss, electrolyte balance, body temperature, or heart rate responses.
Sweat rates, total body water, intracellular water, and thermoregulatory responses remain comparable to placebo, and in some cases, creatine users maintain plasma volume slightly better during early dehydration. Long-term tests in soccer players even suggest that creatine may reduce the risk of cramps and muscle injury, likely because increased intracellular water helps maintain cellular function under heat stress.
Gastrointestinal problems
Gastrointestinal discomfort, including diarrhea, bloating, and stomach upset, is the most commonly reported adverse event, but appears to be dose-related. Large single doses (over 10g at one time) may leave excess creatine unabsorbed in the gut, drawing water into the gut and speeding transit.
Controlled trials have shown that when daily doses are kept between 2 and 5 grams, or when higher doses are divided into multiple smaller portions, symptoms are generally comparable to those of a placebo. Meta-analyses of hundreds of trials involving more than 26,000 participants similarly found no significant difference in gastrointestinal event rates between the creatine and placebo groups. Some discomfort may come from impurities or additives in poorly formulated supplements rather than the creatine itself.
Use of creatine in pregnancy
Although human data are limited, the review notes that animal studies consistently show protective effects of creatine against fetal hypoxia and other stressors, with no maternal or offspring harm observed.
However, because there are no randomized controlled trials in pregnant humans and physiological changes during pregnancy could alter creatine handling, the authors emphasize that creatine supplementation should not currently be recommended in routine prenatal care.
conclusions
According to this review, the evidence overwhelmingly shows that creatine monohydrate is safe when used in recommended doses. Mild gastrointestinal side effects may occur with large single intakes, and more research is needed in pregnant women and people with severe kidney disease.
For the general population, however, creatine remains one of the most well-supported and safest nutritional supplements out there. The authors also stress that only third-party tested creatine products should be used to avoid potential contamination with undeclared or unapproved ingredients.
