Creatyl-l-leucine

Other Names

amide-protected creatine (leucine)CLLcreatine-L-leucine amidecreatinyl-L-leucine

Synopsis

Creatyl-L-Leucine

1. Identity and Chemical Characterization

Chemical Names and Structure

Creatyl-L-leucine is a synthetic, white or beige-colored, crystalline powder with CAS number 1339942-41-4, produced at a minimum purity of 97.0% as measured by high-performance liquid chromatography, with typical analysis results exceeding 99.0% purity. The compound's molecular formula is C₁₀H₂₀N₄O₃, with a molecular weight of 244.29 g/mol. It is also indexed in scientific literature by the abbreviation CLL.

CLL is a creatyl amide that combines creatine and leucine with a covalent amide bond. More specifically, the carboxylic acid group of creatine is covalently linked to an amino acid molecule — specifically the amino group of leucine. This amide-protection of creatine's carboxylic group prevents the carboxylic group and the guanidine group of creatine from reacting and dehydrating to produce creatinine.

Natural Occurrence of Precursor Compounds

Creatine (N-[aminoiminomethyl]-N-methyl glycine) and leucine occur naturally in foods such as meats (beef, chicken, and pork), seafood, and dairy products, with leucine also being found in some grains, soybeans, nuts, beans, seaweed, and sesame. However, creatine and leucine are not known to naturally form bonds with one another endogenously in humans or in nature. Creatyl-L-leucine is therefore entirely a synthetic, novel ingredient with no known natural food source in its conjugated form.

Synthesis

Creatyl-L-leucine (CLL) is synthesized by subjecting L-leucine to a series of chemical processes, resulting in leucine and creatine connected by a covalent bond; thus, CLL is a novel ingredient. The synthesis of creatyl-amide species such as creatyl-L-leucine can be achieved in a manner analogous to creatyl-L-glutamine, except that different amino acids are used as starting materials. Creatyl-L-leucine is a synthetic compound where both creatine and leucine can be produced synthetically or through fermentation processes.

Aqueous Stability and Water Solubility

Amide-protected creatine molecules such as creatyl-L-leucine are substantially stable in aqueous media; the covalent amide bond formed between creatine and the protecting group exhibits unexpectedly improved hydrolysis-stability. Water alone is not sufficient to hydrolyze the amides; in addition to acid or basic conditions, hydrolysis of the amide bond requires the presence of catalysts and/or prolonged heating. This aqueous stability was a principal rationale for the development of CLL as a beverage ingredient, since creatine monohydrate itself has limited water solubility and degrades in acidic aqueous solutions over time.

Common Forms and Preparations in Commerce

CLL appears on commercial beverage labels as "Super Creatine," described as creatyl-L-leucine (creatine bonded to L-leucine), and has been used in energy drinks alongside amino acids and caffeine. Through discovery proceedings in litigation, VPX disclosed that the quantity of creatyl-L-leucine in a can of BANG® ready-to-drink energy drinks is less than 40 mg. The compound has also been included in powdered supplement formulations and pre-workout products. It was trademarked commercially under the name Super Creatine® by Vital Pharmaceuticals, Inc. (VPX).

2. Historical and Traditional Use

Creatyl-L-leucine has no traditional or historical use in any herbal, folk, or cultural medical tradition. CLL is a novel ingredient whose two constituent components — creatine and leucine — have been studied and used extensively by humans with few serious adverse side effects, but to investigators' knowledge no formal toxicological, pharmacokinetic, or human studies on the combined compound had been published prior to the 2018 toxicological assessment.

VPX launched BANG energy drink around 2012, and the original version of BANG contained a related compound, creatyl-L-glutamine (CLG). In 2013, the U.S. Patent and Trademark Office issued U.S. Patent No. 8,445,466 to Jack Owoc, which relates generally to stable aqueous solutions of creatine and methods for their preparation, and covers CLL as a novel ingredient marketed under the trademark "Super Creatine." The ingredient therefore emerged from an industrial patent context rather than from any ethnobotanical or traditional medicinal lineage.

Its constituent molecule creatine has a longer history in both food and clinical science: creatine was first isolated from meat extract in 1832, and creatine monohydrate has been studied as a dietary supplement since the early 1990s. L-leucine, similarly, is a well-characterized essential branched-chain amino acid (BCAA) that has been studied in the context of muscle protein synthesis for decades. For centuries, diets rich in creatine and leucine were associated with muscle strength and vitality, and meat and legumes — natural sources of these compounds — were encouraged by healers to address fatigue and muscle weakness. However, none of this traditional history applies to the chemically bonded CLL molecule itself.

3. Key Constituents and Proposed Mechanisms of Action

Constituent Molecules

Creatine component: Creatine is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase. The vast majority (approximately 95%) of creatine is stored in skeletal muscles, with other tissues with high creatine and phosphocreatine levels including heart muscle, retina, brain, and brown adipose tissue. Creatine absorbed from the intestinal tract is transported in the blood, where it mixes with creatine of endogenous origin; creatine is transported from the bloodstream through the blood-brain barrier (BBB) via the creatine transporter (CRT), and after its transport into the brain's extracellular fluid, creatine is actively taken up by neurons and oligodendrocytes, but not astrocytes.

L-Leucine component: Leucine is a branched-chain amino acid involved in the regulation of skeletal muscle protein synthesis as well as influencing other physiological processes such as enabling adenosine triphosphate generation, insulin secretion from the pancreatic β-islet cells, and activation of cell signaling pathways.

Proposed Mechanism for CLL

Some side effects reported with creatine monohydrate supplementation have stimulated research into new potential molecules that could provide bioavailable creatine, and creatyl-L-leucine has been proposed as a potential dietary ingredient that may potentially provide bioavailable creatine.

The key proposed mechanism for CLL — that it would serve as a stable precursor that hydrolyzes in vivo to release free creatine and L-leucine — has been the central focus of available scientific investigation. The amide bond linking creatine and leucine in CLL is structurally different from conventional peptide bonds found between amino acid residues. Peptide bonds are normally stable under physiological conditions, only being hydrolyzed by protease or peptidase enzymes. However, the chemical structure of CLL is not likely to be recognized by the active sites of protease or peptidase enzymes, given the very different structure of creatine when compared to amino acid residues in a peptide. Thus, it is highly unlikely that a peptidase enzyme or other enzyme would bind to CLL to catalyze hydrolysis to creatine and leucine.

A related analog, creatyl-L-glutamine, has provided indirect evidence: an unpublished simulated gastric digestion study on creatyl-L-glutamine indicated that only 27% of the compound was hydrolyzed; however, no digestion or pharmacokinetic data were located regarding CLL at the time of the 2018 toxicological assessment.

The patent protecting CLL explicitly identifies one of its core attributes as stability rather than rapid enzymatic release: the amide-protected creatine molecules, such as creatyl-L-glutamine and creatyl-L-leucine, are substantially stable in aqueous media, and the covalent amide bond formed between creatine and the protecting group exhibits unexpectedly improved hydrolysis-stability. This property, while commercially advantageous for liquid beverage formulations, simultaneously raises questions about whether CLL can be hydrolyzed efficiently enough after ingestion to deliver physiologically meaningful amounts of creatine.

4. Scientific Evidence by Area of Use

4.1 Muscle Creatine Accumulation and Ergogenic Performance

Human/Clinical Evidence:

The most methodologically rigorous published investigation of CLL's physiological effects in humans is a randomized, double-blind, placebo-controlled trial published in 2022. Twenty-nine healthy men (n = 17) and women (n = 12) consumed 5 g/day of either creatine monohydrate (n = 8), CLL (n = 11), or placebo (n = 10) for 14 days in a randomized, double-blind design; participants completed three bouts of supervised resistance exercise per week, and muscle biopsies were collected before and after the intervention for quantification of muscle creatine.

The authors reported that creatine monohydrate supplementation significantly increased muscle creatine content within 14 days of supplementation, but no significant changes in muscle creatine content were observed for the placebo or CLL groups.

This trial elicited a published commentary: a comment published in the same journal (Escalante and St. Mart, 2023) highlighted what the commentators described as a critical flaw in the design of the study, drew attention to other study limitations or inconsistencies, and pointed to a calculation error in the discussion. The original authors published a reply. The exchange underscores the limitations of the existing evidence base, including the small sample sizes in each group (8, 11, and 10 participants respectively) and the limited duration of 14 days.

While conflicting evidence on the bioavailability of CLL has been reported by da Silva, the author did acknowledge that it could not be concluded that CLL was not absorbed due to the limit of detection of the high-performance liquid chromatography assay.

Animal Evidence:

Rats were deprived of dietary creatine for a period of two weeks and then given one of three treatments: a control creatine-free diet, a diet supplemented with creatine monohydrate, or a diet with an equimolar amount of creatyl-L-leucine for one week. When compared to the control and the creatine monohydrate-supplemented diet, creatyl-L-leucine supplementation resulted in no bioaccumulation of either creatyl-L-leucine or creatine in tissue. Dosing used in the animal study was 0.4% (w/w) creatine monohydrate and 0.656% (w/w) creatyl-L-leucine, with equimolar creatine equivalents, and n = 8 per group.

This study assessed the effects of feeding rats either a control diet, a diet containing 4.0 g/kg/day of creatine monohydrate, or a diet containing 6.56 g/kg/day of CLL for 7 days on arterial delivery of creatine, tissue uptake, and storage. According to the researchers, for a 70 kg individual this would equate to a dose of 17.6 g/day of creatine monohydrate and 28.9 g/day of CLL providing equimolar amounts of creatine — if CLL degraded into creatine.

Evidence Strength Assessment: The evidence against CLL functioning as a meaningful bioavailable source of creatine is currently more robust than the evidence in its favor. Two independent studies — one preclinical (da Silva, 2022, rat model) and one human clinical RCT (Askow et al., 2022) — both failed to demonstrate bioaccumulation or muscle creatine elevation following CLL supplementation. Both are limited in scope (one species, short durations, small human sample sizes), but their convergent findings are consistent with the known chemical stability of the CLL amide bond. No independent positive clinical trials demonstrating CLL's efficacy as a creatine source have been published in the peer-reviewed literature.

4.2 Cognitive Function and Brain Fuel Claims

Promotional claims by VPX associated with the "Super Creatine" trademark — including assertions that CLL crosses the blood-brain barrier more effectively than creatine, that it is "potent brain and body fuel," and that it may address neurodegenerative diseases — were at the center of multiple lawsuits. The class-action complaint filed in 2018 alleged that VPX represented that the drinks contain Super Creatine that is allegedly 20 times more effective at reaching the brain than regular creatine, when according to plaintiffs there is no such thing as "Super Creatine" and the ingredient called "Super Creatine" is actually creatyl-L-leucine, which is not creatine at all.

Independent researchers and expert witnesses in the litigation examined Super Creatine, chemically identified as Creatyl-L-Leucine. Their findings indicated that Creatyl-L-Leucine is not the same as creatine monohydrate; the body does not metabolize it the same way as standard creatine; Bang Energy provided no clinical trials showing the claimed cognitive benefits; and the amounts present in a single can were too small to produce any measurable creatine effect.

No studies were ever shown to the jury by VPX backing up its past claims about the benefits of super creatine.

Evidence Strength Assessment: There are no published peer-reviewed human clinical trials evaluating creatyl-L-leucine's effects on cognitive function, brain creatine levels, or neurological outcomes. The claims that CLL provides cognitive benefits superior to creatine monohydrate have no published scientific support. Whether CLL in any form crosses the blood-brain barrier has not been studied in humans.

4.3 Athletic Performance, Muscle Strength, and Body Composition

No independent peer-reviewed clinical trial has demonstrated that CLL improves athletic performance, muscle strength, power output, or body composition in humans. The sole published human RCT (Askow et al., 2022) was designed specifically to assess muscle creatine content as an intermediate outcome, not functional performance endpoints. Given that CLL did not raise muscle creatine in that trial, a downstream effect on creatine-dependent performance outcomes would not be expected. Currently, the direct scientific validation of creatyl-L-leucine is limited, and there is a lack of peer-reviewed clinical studies specifically evaluating its safety, bioavailability, or ergogenic effects compared to standard creatine monohydrate or L-leucine supplementation.

Evidence Strength Assessment: No human clinical evidence for ergogenic efficacy. Evidence is absent rather than negative.

4.4 Comparison to Creatine Monohydrate and Other Novel Creatine Forms

A 2011 paper providing an overview of the bioavailability, efficacy, and regulatory status of creatine monohydrate as well as other "novel forms" of creatine concluded that no other purported form of creatine had been shown to be a more effective source of creatine than creatine monohydrate, and that most purported "forms" of creatine being marketed were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy.

A critical review of creatine and related compounds updated these conclusions: unsupported misrepresentations about the effectiveness and safety of various "forms" of creatine have continued.

5. Body Systems Associated With CLL (Based on the Literature)

Skeletal muscle: CLL was hypothesized to deliver creatine to muscle tissue to support phosphocreatine resynthesis and ATP buffering. Available evidence does not support this hypothesis; no significant changes in muscle creatine content were observed for the CLL group in the only published human RCT.
Central nervous system / brain: The brain and skeletal muscle have a high energy demand, of which creatine is an important regulator; creatine acts as both a spatial and temporal energy buffer and reduces oxidative stress and inflammation. CLL was promoted as a superior vehicle for brain creatine delivery, but this has not been tested or validated in humans.
Cardiovascular system: Heart muscle is among the tissues with high creatine and phosphocreatine levels. No CLL-specific cardiovascular studies exist.
Gastrointestinal system: An unpublished simulated gastric digestion study on the related analog creatyl-L-glutamine indicated that only 27% of the compound was hydrolyzed, though no digestion or pharmacokinetic data were reported for CLL.

6. Dosage Forms and Reported Dosages

Dosages of CLL used in the published literature are as follows:

Human clinical trial (Askow et al., 2022): Twenty-nine healthy men and women consumed 5 g/day of either creatine monohydrate, CLL, or placebo for 14 days in a randomized, double-blind design.
Animal study (da Silva, 2022): Rats received an AIN-93G diet supplemented with 0.656% (w/w) creatyl-L-leucine for 7 days following a 14-day creatine depletion phase. The researchers noted that for a 70 kg individual, this rat dose would equate to approximately 28.9 g/day of CLL providing equimolar amounts of creatine — if CLL fully degraded into creatine.
Toxicological study (Reddeman et al., 2018): Creatyl-L-leucine was administered orally (gavage) to Hsd.Han Wistar rats at doses of 1,250, 2,500, and 5,000 mg/kg bw/d in a 90-day repeated-dose toxicity study.
Genotoxicity testing (Reddeman et al., 2018): There was no genotoxic activity observed in the in vivo mammalian micronucleus test at concentrations up to the limit dose of 2,000 mg/kg bw/d.
Commercial beverage (BANG® energy drink): Through litigation discovery, VPX disclosed that the quantity of creatyl-L-leucine in a can of BANG® ready-to-drink energy drinks is less than 40 mg.

No human pharmacokinetic dose-finding studies or dose-response studies for CLL have been published in peer-reviewed literature.

7. Safety Considerations

Preclinical Toxicology (Animal Studies)

A battery of toxicological studies was conducted to investigate the genotoxicity and repeated-dose oral toxicity of creatyl-L-leucine, a synthetic compound, in rats in accordance with internationally accepted guidelines.

Genotoxicity: There was no evidence of mutagenicity in a bacterial reverse mutation test and in an in vitro mammalian chromosomal aberration test. There was no genotoxic activity observed in an in vivo mammalian micronucleus test at concentrations up to the limit dose of 2,000 mg/kg bw/d.

CLL was not mutagenic under the applied conditions of the bacterial reverse mutation test at concentrations up to 5,000 µg/plate or up to the maximum recommended concentration of 2,000 μg/mL, with or without metabolic activation in V79 Chinese hamster lung cells. Under the in vivo conditions of the mammalian micronucleus test, CLL did not exhibit genotoxic potential at doses up to 2,000 mg/kg bw in male Crl:NMRI BR mice.

Repeat-dose oral toxicity: CLL did not cause adverse effects and no target organs were identified in male or female Hsd.Han Wistar rats after the consecutive 90-day repeated-dose gavage administration of 1,250, 2,500, or 5,000 mg/kg bw/d. Based on the observations made in this study, a NOAEL was estimated as 5,000 mg/kg bw/d in male and female Hsd.Han:Wistar rats.

Absence of Human Safety Data

While individually creatine and leucine have been studied and used extensively by humans with few serious adverse side effects, to investigators' knowledge no formal toxicological, pharmacokinetic, or human studies on the combined compound had been published at the time of the 2018 safety assessment. The only published human study (Askow et al., 2022) was primarily designed to assess efficacy (muscle creatine content) rather than systematically characterize safety outcomes, and involved a 14-day exposure period in a small cohort. No long-term human safety studies for CLL have been published.

Compound Identity and Interactions

Creatine and leucine are not known to naturally form bonds with one another endogenously in humans or in nature, meaning there is no established precedent for endogenous CLL metabolism. The absence of known enzymatic pathways for CLL hydrolysis under physiological conditions raises open questions about what metabolites, if any, are generated after ingestion. No specific drug interaction studies for CLL have been published.

Regulatory and Legal Context

The marketing of CLL as "Super Creatine" generated extensive regulatory and legal scrutiny. A class-action lawsuit filed against VPX Sports and its founder in September 2018 alleged, among other things, that the company represented that the ingredient called "Super Creatine" is a new compound allegedly 20 times more effective at reaching the brain than regular creatine, when according to the plaintiffs there is no such thing as "Super Creatine" and the ingredient is really creatyl-L-leucine, which is not creatine at all.

A $293 million jury verdict was returned in September 2022 against Bang Energy owner Vital Pharmaceuticals (VPX) for falsely advertising the health benefits of the ingredient super creatine; the civil lawsuit had been brought by Monster Beverage in California. Following this verdict, the brand announced that the words "Fuel Your Destiny" would replace "Super Creatine" at the top center of the brand's cans; however, the drink would still contain creatyl-L-leucine according to VPX's CEO.

One of VPX's own expert witnesses, Guillermo Escalante, opined that CLL is a form of creatine, but further opined that CLL could be a form of a creatine derivative and that it has not been sufficiently studied to conclude that this is the case.

References

Health Conditions

Health conditions that Creatyl-l-leucine may help support.

No conditions available.

Body Systems

Body systems that Creatyl-l-leucine may help support.

No body systems available.