Table 2.

Efficacy of creatine in clinical settings.

Author Year	Subjects	Design	Duration	Dosing Protocol	Primary Variables	Results	Adverse Events
Sipila et al. 1981 [57]	7 (3 adolescents) patients with gyrate atrophy of retina	Open label treatment intervention	12 months	1.5 g/day	Visual acuity, muscle fiber characteristics, laboratory markers of creatine metabolism	Visual acuity; ↑ Thickness of Type II muscle fibers	No side effects reported
Vannas-Sulonen et al. 1985 [58]	13 patients (9 male, 4 female) between ages of 6–31 years diagnosed with gyrate atrophy of the choroid	Prospective, open-label cohort	36–72 months	0.25–0.5 g dose 3×/day	Morphological and eye function assessments	Cr supplementation did not prevent normal deterioration; ↓ Muscle atrophy, primarily in type II fibers	None reported
Walter et al. 2000 [59]	36 patients with multiple types of muscular dystrophies (overall mean age: 26 ± 16 years) 8 patients with Duchenne dystrophy (mean age: 10 ± 3 years)	Randomized, double-blind, placebo-controlled	8 weeks	10 g/day (adults) 5 g/day (children)	Muscular performance, neuromuscular symptoms score, vital capacity and qualitative assessments	↑ (3%) in muscle strength; ↑ (10%) in neurological symptoms. Children tended to experience greater strength changes.	None reported. Indicated to be well-tolerated.
Braegger et al. 2003 [60]	18 cystic fibrosis patients (7 F, 11 M) ranging in age from 8–18 years	Prospective open-label pilot	Supplemented for 12 weeks; monitored for 24–36 weeks	12 g/day for 1st week; 6 g/day for remaining 11 weeks	Lung function, strength, and clinical parameters	Lung function or sweat electrolytes. ↑ (18%) in peak isometric strength	One patient experienced transient muscle pain; No other side effects
Louis et al. 2003 [61]	15 boys with muscular dystrophy (mean age: 10.8 ± 2.8 years)	Double-blind, placebo-controlled, cross-over study design	3 months, with 2 months washout	3 g/day	Muscle function, densitometry, markers of hepatic and renal function, magnetic resonance spectroscopy	↑ MVC by 15% ↑ TTE (~2×) ↑ TJS ↑ LS and WB BMD in ambulatory patients ↑ NTx/creatinine ratio in ambulatory patients	No changes in liver or kidney markers
Tarnopolsky et al. 2004 [45]	30 boys with Duchenne muscular dystrophy; mean age: 10 ± 3 years; height: 129.2 ± 16.0 cm; weight: 35.3 ± 15.8 kg	Double-blind, randomized, crossover trial	4 months	0.10 g/kg/day	Pulmonary function, strength, body composition, bone health, task function, blood & urinary markers	↑ handgrip strength, fat-free mass, and bone markers functional tasks or activities of daily living	None
Escolar et al. 2005 [49]	50 ambulatory steroid naïve boys with Duchenne Muscular Dystrophy (mean age: 6 years)	Double-blind, placebo-controlled, randomized	6 months	5 g/day of creatine powder, 0.3 mg/kg of glutamine (×2 per day), or placebo	Manual muscle performance, quantitative muscle testing, time to rise	primary or secondary outcomes measures	Deemed safe and well-tolerated with no side effects reported.
Sakellaris et al. 2008 [62]	39 children/adolescents following traumatic brain injury	Open-label pilot study	6 months	0.4 g/kg/day	Duration of amnesia, duration of intubation, and intensive care unit stay post traumatic brain injury	↓ Amnesia ↓ Intubation period ↓ Intensive care unit stay	None
Bourgeois et al. 2008 [63]	9 children with lymphoblastic leukemia during chemotherapy (in treatment group); mean age of 7.6 years, 50 healthy children as history controls	Cross sectional, mixed cohort designs	16 weeks	0.1 g/kg/day	Height, weight, BMI, BMD, BMC, FFM, %BF, serum creatinine	↑ %BF and BMI	None reported
Banerjee et al. 2010 [9]	33 ambulatory male patients with Duchenne muscular dystrophy	Randomized, placebo-controlled, single-blind trial	8 weeks	Cr, 5 g/day (n = 18)	Cellular energetics, manual muscle test score and functional status	↑ in PCr/Pi ratios	None reported
Van de Kamp et al. 2012 [16]	9 boys with creatine transporter defect	Long-term follow-up investigation	4–6 years	Cr (400 mg/kg/day) and L-arginine (400 mg/kg/day)	Locomotor and personal social IQ subscales	Initial ↑ in locomotor and personal social IQ subscales; No lasting clinical improvement was recorded	No adverse events were reported.
Hyashi et al. 2014 [13]	15 participants with childhood systemic lupus erythematosus	Double-blind, placebo controlled, cross-over design	12 weeks with 8 week washout period	0.1 g/kg/day	Muscle function, body composition, biochemical markers of bone, aerobic conditioning, quality of life	intramuscular PCr, muscle function, and aerobic conditioning parameters, body composition, quality of life	laboratory parameters; No side effects reported
Solis et al. 2016 [12]	Patients with juvenile dermatomyositis (mean age: 13 ± 4 years)	Randomized, double-blind, placebo-controlled, crossover trial	12 weeks	0.1 g/kg/day	Primary: muscle function Secondary: body composition, biochemical markers of bone remodeling, cytokines, laboratory markers of kidney function, aerobic conditioning, and quality of life	Muscle function, intramuscular PCr content, or other secondary outcomes measures	No side efforts reported. Markers of kidney function
Kalamitsou et al. 2019 [64]	22 children (9 F, 13 M) with refractory epilepsy ranging in age from 10 months to 8 years	Prospective cohort	3–12 months follow-up	0.4 g/kg/day creatine + ketogenic diet	Proportion of responders to ketogenic diet	6/22 (27%) responded to creatine addition to ketogenic diet	None reported, well-tolerated with no exacerbations of underlying pathology
Dover et al. 2020 [65]	13 (7 F, 6 M) patients ranging in age from 7–14 years with juvenile dermatomyositis; 25.6–64.6 kg; 14.3–22.9 kg/m2	Randomized, double-blind, placebo-controlled	6 months	Up to 40 kg was 150 mg/kg/day >40 kg was 4.69 g/m2/day	Safety and tolerability muscle function, disease activity, aerobic capacity, muscle strength	in muscle function, strength, aerobic capacity, fatigue, physical activity ↓ in muscle pH following exercise	No adverse events reported

= Creatine supplementation resulted in no change in the target outcome; ↑ = Creatine supplementation resulted in an increase in the target outcome; ↓ = Creatine supplementation resulted in a decrease (directional) in the target outcome. BMI = body mass index; FFM = fat-free mass; %BF = body fat percentage; TJS = total joint stiffness; TTE = time to exhaustion; g/d = grams per day; g/kg/d = grams per kilogram of bodyweight per day; mg/kg/d = milligrams per kilogram of bodyweight per day; PCr = phosphocreatine. MVC = maximum voluntary contraction; NTx = N-terminal telopeptide of type I collagen; LS = lumbar spine; WB = whole body; BMD = bone mineral density; BMC = bone mineral content; Pi = inorganic phosphate.