Searching for a better formulation to enhance muscle bioenergetics: A randomized controlled trial of creatine nitrate plus creatinine vs. creatine nitrate vs. creatine monohydrate in healthy men

Abstract

A novel creatine blend (creatine nitrate mixed with creatinine, CN‐CRN) has been anecdotally suggested to be superior to traditional creatine formulations for bioavailability and performance. However, does CN‐CRN supremely affects creatine levels in the blood and skeletal muscle of healthy humans remain currently unknown. This randomized, controlled, double‐blind, crossover trial evaluated the acute effects of single‐dose CN‐CRN on serum creatine levels, and 5‐days intervention with CN‐CRN on skeletal muscle creatine and safety biomarkers in healthy men. Ten healthy young men (23.6 ± 2.9 years) were allocated to receive either CN‐CRN (3 grams of creatine nitrate mixed with 3 grams of creatinine), pure creatine nitrate (3 grams, CN), or regular creatine monohydrate (3 grams, CRM) by oral administration. We found that CN‐CRN resulted in a more powerful rise in serum creatine levels comparing to either CN or CRM after a single‐dose intervention, as evaluated with the area under the concentration–time curve calculation (701.1 ± 62.1 (µmol/L) × min versus 622.7 ± 62.9 (µmol/L) × min versus 466.3 ± 47.9 (µmol/L) × min; p < .001). The peak serum creatine levels at 60‐min sampling interval were significantly higher in CN‐CRN group (183.7 ± 15.5 µmol/L), as compared to CN group (163.8 ± 12.9 µmol/L) and CRM group (118.6 ± 12.9 µmol/L) (p < .001). This was accompanied by a significantly superior increase in muscle creatine levels after CN‐CRN administration at 5‐days follow‐up, as compared to CN and CRM, respectively (9.6% versus 8.0% versus 2.1%; p = .01). While 2 out of 10 participants were found to be nonresponsive to CN intervention (20.0%) (e.g., no amplification in muscle creatine levels found at 5‐days follow‐up), and 3 participants out of 10 were nonresponsive in CRM trial (30%), no nonresponders were found after CN‐CRN administration, with individual upswing in total muscle creatine varied in this group from 2.0% (lowest increment) to 16.8% (highest increment). Supplemental CN‐CRN significantly decreased estimated glomerular filtration rate (eGFR) at 5‐days follow‐up, as compared to other interventions (p = .004), with the average reduction was 14.8 ± 7.7% (95% confidence interval; from 9.3 to 20.3). Nevertheless, no single participant experienced a clinically relevant reduction in eGFR (< 60 ml/min/1.73 m2) throughout the course of the trial. Liver enzymes remained in reference ranges throughout the study, with no participant experienced high liver blood tests (e.g., AST > 40 units per L or ALT >56 units per L). Besides, no participant reported any major side effects during the trial, while the odors of CN‐CRN and CN formulations were considered somewhat unpleasant in 8 out of 10 participants (80.0%). Our results suggest that CN‐CRN is a preferred and relatively safe alternative to traditional creatine formulations for improved creatine bioavailability in the blood and skeletal muscle after single‐dose and 5‐days interventions.

Analysis of the efficacy, safety, and cost of alternative forms of creatine available for purchase on Amazon.com: are label claims supported by science?

“…Some evidence to suggest supplementation provides an ergogenic effect for muscle endurance, but since it was unrelated to changes in muscle creatine content the benefit may come from the nitrate as opposed to creatine. Remains to be determined if supplementation has any additional benefit than simply co-ingesting CM with a source of nitrate [ 12 , 17 , 28 , 29 , 35 , 50 ] Magnesium Creatine Chelate Some Evidence No evidence it is more bioavailable, efficacious, and/or safer than CM and limited evidence it is as effective as CM to increase strength, power, and muscle endurance [ 6 , 35 , 55 , 68 ] Creatine Anhydrous Not Provided No data available, but this compound is 100% creatine and likely has similar effects to CM Free Acid Creatine Not Provided Not available …”

Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review

“…These findings suggest that CrN can be a bioavailable source of creatine proportional to the amount of creatine delivered during the loading phase (i.e., 54.6 g for CrN-High versus 73.8 g for CrM), but not more bioavailable than CrM when equivalent doses are ingested. On the other hand, Ostojic et al [ 209 ] conducted a study evaluating the effects of CrM and CrN supplementation on MRS determined skeletal muscle creatine content and markers of health. In a randomized and crossover manner with a 7 day washout period, participants ingested a placebo, 3 g/day of CrN, 3 g/day of CrM, or 3 g/day of CrN + 3 g/day of CrM for 5 days.…”

The Development of Alternative Dosage Form for Creatine Monohydrate: A Floating Tablet

“…However, its delivery encounters several limitations in terms of its enormous doses, physicochemical properties, transport mechanisms, and compound stability. The dose of creatine is relatively large, namely 20 g/day for loading doses, 2-5 g/day for maintenance doses, and 20-30 g/day for neurodegenerative therapy purposes [2,3].…”