What are the potential side effects of creatine (creatine monohydrate) supplementation in a healthy adult without pre-existing kidney disease or other significant medical conditions?

Creatine Monohydrate Side Effects

Creatine monohydrate supplementation is generally safe in healthy adults without pre-existing kidney disease, with the most common side effect being transient water retention causing 1-2 kg weight gain, and no significant adverse effects on kidney function, liver function, or other organ systems when used at recommended doses. 1, 2, 3

Common and Expected Side Effects

Water Retention and Weight Gain

• The primary side effect is transient water retention in early stages of supplementation, typically resulting in 1-2 kg increase in body mass 1, 4
• This weight gain is due to increased intracellular water content in muscle cells or increased protein synthesis, not fat accumulation 1
• The effect is most pronounced during loading phases (20 g/day) and diminishes during maintenance dosing (3-5 g/day) 1

Gastrointestinal Effects

• Mild gastric discomfort, nausea, or diarrhea can occur, particularly at high doses (>10 g single dose) 3, 4
• These effects are dose-dependent and not universally experienced 3
• Taking creatine with food or dividing doses throughout the day (e.g., 5g four times daily during loading) minimizes GI distress 1

Debunked Safety Concerns

Kidney Function

• Multiple studies demonstrate no adverse effects on kidney function in healthy individuals, even with long-term use (5 days to 5 years) at doses ranging from 5-30 g/day 2, 3
• A prospective case study showed creatine supplementation (20g/day for 5 days, then 5g/day for 30 days) in a young man with a single kidney did not change measured GFR (51Cr-EDTA clearance: pre 81.6 vs post 82.0 mL/min/1.73m²) 5
• Serum creatinine may increase by 0.2-0.3 mg/dL due to increased dietary creatine conversion to creatinine, not actual kidney damage 6, 5
• This creates a false appearance of kidney dysfunction when using creatinine-based eGFR calculations 6, 5

Dehydration and Muscle Cramps

• Claims that creatine causes dehydration or muscle cramps during exercise are unsupported by controlled studies 3
• Evidence suggests creatine may actually reduce the incidence of muscle cramps and assist in maintaining thermoregulatory balance 3
• No significant effects on hydration status or thermoregulation have been demonstrated 3

Cancer Risk

• Theoretical concerns about creatine forming carcinogenic compounds are not supported by available research 3
• No link between creatine supplementation and cancer has been established 3

Rare or Theoretical Concerns

Hepatic Effects

• When combined with other supplements or taken at higher than recommended doses for several months, isolated cases of liver complications have been reported 4
• Standard dosing in healthy individuals shows no adverse effects on hepatic function 7

Metabolite Production

• Short-term high-dose supplementation (20 g/day to 0.3 g/kg/day for 5 days to 2 weeks) stimulates production of methylamine and formaldehyde in urine 2
• Despite theoretical cytotoxic potential, there is no definite clinical evidence of adverse effects from these metabolites on kidney function 2

Critical Contraindications and Cautions

Pre-existing Kidney Disease

• Creatine supplementation should be avoided in individuals with pre-existing kidney disease (GFR <45 mL/min/1.73m²) or those at risk for kidney dysfunction 6, 2
• The American Journal of Kidney Diseases explicitly discourages creatine use in kidney donors with solitary kidneys due to need to preserve remaining renal function 6

Pregnancy

• Creatine should be avoided in pregnancy due to lack of safety data in this population 3

Monitoring Considerations

• If kidney function assessment is needed during creatine supplementation, use cystatin C-based GFR or measured GFR rather than creatinine-based eGFR 6
• Creatinine-based calculations will falsely suggest kidney dysfunction due to increased creatinine generation from supplementation 6, 5

Clinical Pitfalls to Avoid

Misdiagnosis of Kidney Disease

• A single elevated serum creatinine in the context of creatine supplementation does not establish kidney disease diagnosis 6
• Discontinue creatine and recheck creatinine in 1-2 weeks to assess true baseline kidney function 6
• After cessation, creatine levels return to normal in approximately 4-6 weeks 1

Combining with Nephrotoxic Agents

• Avoid combining creatine with NSAIDs, high-dose protein supplements, or other nephrotoxic medications, as this may unmask subclinical kidney stress 6

Safety Profile Summary

• No deaths or serious adverse outcomes have been reported in systematic reviews of creatine supplementation in females (951 participants across 29 studies) 7
• No statistically significant differences in total adverse events (RR 1.24,95% CI 0.51-2.98), gastrointestinal events (RR 1.09,95% CI 0.53-2.24), or measures of renal/hepatic function compared to placebo 7
• The evidence consistently supports that creatine monohydrate is safe when used at recommended doses in healthy individuals without pre-existing kidney disease 2, 3, 7