Creatine Ethyl Ester: The Best Creatine or a Supplement Fallacy?

By James Collier, MuscleTalk Co-Owner and Nutrition Consultant

Creatine ethyl ester (CEE) is a derivative of the nutritional supplement creatine used as an aid for athletic performance in sports and muscle development in bodybuilding. Creatine is one of the most popular sports supplements available, and naturally it is a compound used as an energy replenisher. Its chemical name is methylguanido-acetic acid, formed from the amino acids arginine, methionine and glycine. The most common form of supplementary creatine available is creatine monohydrate. For more detailed general information about creatine, please see our Creatine FAQs article

CEE is most commonly available as creatine ethyl ester hydrochloric acid (CEE HCl) in powder, capsule or tablet form. As a supplement, the compound was developed, patented and licensed through UNeMed, the technology transfer entity of the University of Nebraska Medical Center, and has been developed and sold under numerous brand names by different supplement companies.

Since its launch just a few years ago, there have been many claims made by supplement companies that CEE is the new revolutionary creatine, and is far superior to creatine monohydrate. These claims have been backed up by articles in bodybuilding and fitness magazines and on websites, posts on internet forums and people's claims that CEE gives better results. The claims revolve around CEE's supposed better absorption rate and longer half-life than creatine monohydrate due to the fact that it is slightly more lipophilic. However these claims have not yet been conclusively proven by independent research and they seem to have been self perpetuating and may be nothing more than the successful results of cleverly targeted marketing.

This article examines the arguments for and against CEE, to provide information for you to make up your own mind if CEE is better than creatine monohydrate.

Arguments against CEE

  • CEE and Creatine Kinase
    CEE is claimed to be a true covalently bonded ester and is absorbed into blood as a molecule wholly intact. It is claimed that this is the reason why CEE is superior to monohydrate. However, inside cells CEE cannot be hydrolysed by the enzyme creatine kinase (CK - which catalyses free creatine) and may infact inhibit the enzyme. Therefore in theory, this would make CEE toxic to all organs and tissues which contain CK, including brain, heart and muscle, which it clearly isn't as there have been no reported deaths or even ill health. So this argument against CEE must be flawed.
  • Breakdown to Creatinine
    CEE is hydrolysed to the breakdown product creatinine after it has been absorbed from the digestive system. Child & Tallon (2004) studied the conversion of creatine to creatinine in the stomach. They compared three commercial creatine products during degradation in acidic solutions in order to mimic the stomach conditions. Creatine availability was assessed by immediately assaying for free creatine, CEE and creatinine. After 30 minutes incubation only 62-73% of the initial CEE was left from the CEE products, whereas more than 99% of the creatine remained available from the monohydrate product. These reductions in CEE availability were accompanied by substantial creatinine formation, without the appearance of free creatine. After 120 minutes there had been even further degredation of the CEE, while more than 99% of the creatine remained available from monohydrate.

    CEE is claimed to provide several advantages over creatine monohydrate because of increased solubility and stability. However it appears that the addition of the ethyl group to creatine actually reduces acid stability and accelerates its breakdown to creatinine. This substantially reduces creatine availability in its esterified form and as a consequence CEE is inferior to creatine monohydrate as a source of free creatine.

    CEE offers no advantage over creatine monohydrate which has a bioavailability of nearly 100%, i.e. nearly all is absorbed. Infact if hydrolysis of CEE is less than 99% then it must be inferior to monohydrate, and in the case of hydrolysis there are no circumstances in which it could be better than the monohydrate in increasing tissue creatine levels.

  • CEE is not a true covalently bonded ester
    This means that it is infact a scam with the compound ionising in solution to free creatine, as does the monohydrate and all salts of creatine. In this case CEE would again represent no advantage over creatine monohydrate, except to the seller who can double the price.
  • Lack of Simple Experiments
    The failure of the US sports nutrition community (industry and universities) to call for closer examination of CEE seriously questions its credibility in the eyes of many scientists. A simple water solvation test would answer whether or not it was a covalent or ionisable derivative of creatine, a short experiment taking less than an hour! Investigation of whether CEE is a competitive or non-competitive inhibitor of creatine kinase would take just 2-3 hours. If either of these occurred then clearly CEE must be investigated in at least two species to investigate lethality and potential organ damage. If on the other hand CEE is ionisable then there is no reason why a bioavailability study should not be undertaken comparing it, on a molar/molar basis, to creatine monohydrate. My guess is that plasma AUC would be identical. Again a very simple study.

    None of this is rocket science but could spare a few lives, if the manufacturers' claims on the absorption of CEE are to be believed.

  • FDA Concerns
    CEE is young, and was launched only as few years ago, and from day one the US Food and Drug Administration (FDA) had concerns. One of the original companies (MRI) who produced CEE HCl in 2004 contacted the FDA for approval (MRI 2004), and back then they (the FDA) noted that CEE HCl doesn't really fit into the definition of a 'supplement' as a 'dietary ingredient' (FDA 2004). They also noted concerns as to the design of trials for CEE HCl which failed to provide data showing that creatine levels are increasing as CEE dissociates and diffuses from the gut into the blood, which did not clearly demonstrate the relative concentration of CEE, creatine, and ethanol between the gut and blood especially during the first three hours after intake (ChemPharma Int'l). It was unclear how creatinine levels in the urine could be detected yet there were no recorded measurements for creatine in the blood during the first 190 minutes of the experiment. The FDA were concerned about the validity of the conclusion that CEE HCl was rapidly absorbed and dissociated into creatine and ethanol before being available to the tissues. In addition, it was noted that the long term toxicological effects of doses higher than three grams per day are unknown.
  • CEE Powder is Cariogenic
    CEE HCl is an acid, so when in contact with the teeth, it is likely to case dental erosion. Obviously this only refers to the powder version of CEE HCl, so to avoid this stick to creatine monohydrate or capsule forms of CEE.
  • Gastro-Intestinal Problems
    Some people claim to have suffered stomach upset and discomfort with CEE, whereas they have not with creatine monohydrate. However this is merely anecdotal claims, indeed creatine monohydrate is known for its side effect of nausea.
  • Creatine Doesn't 'Work' for Everyone
    It's commonly claimed, although not backed by science, that creatine, including CEE and creatine monohydrate, doesn't work for about one in four to one in six people. This may be due to lower levels of CK, or some other as yet unknown reason.
  • Price
    CEE is more expensive to buy that creatine monohydrate; considerably more. However to produce it, there is little difference. Sceptics claim that companies charge more to initiate perceived benefits over monohydrate.

Arguments For CEE

  • Higher Plasma Delivery Rates
    The Medical Research Institute (MRI - CA, USA) claim that the CEE in their product (CE2™) provides greater solubility in lipids, leading to improved absorption. Similarly SAN (San Corporation, CA, USA) claim that the CEE in their product (San CM2 Alpha™) avoids the breakdown of creatine to creatinine in stomach acids. Ultimately it is claimed that CEE products provide greater absorption and efficacy than creatine monohydrate. However, to date none of these claims have been evaluated by an independent, or university laboratory and no comparative data are available between CEE and monohydrate.
  • Anecdotal Claims
    There is no doubt creatine monohydrate 'works' – it's backed by a large amount of scientific research. However so many experienced creatine users do claim CEE is better. It's claimed to be better primarily because of permeability and lower preplasma hydrolysis rates, but it may be a case of perceived benefits as the results of clever marketing and judging quality by price.
  • Convenience
    Most creatine monohydrate is available in powder form, and most CEE is in capsule or tablet form. Both are available in other forms, but seem to be less available that way, indeed the monohydrate capsules are much more expensive, akin to the price of CEE capsules. People prefer pills to powders so it stands to reason they'll opt for the CEE capsules.

Creatine Ethyl Ester V Creatine Monohydrate

You'll notice there are surprisingly few arguments in favour of CEE, and those that are there are weak. Yet it remains a very popular product. This is because the anecdotal evidence for it is very strong; a large number of users, who got on well with creatine monohydrate, are positive their gains were even better with CEE. But anecdotal evidence is weak evidence... isn't it? Yes it is, but it's also very powerful evidence, and couple this with strong marketing campaigns from the supplement companies, you'll have an argument in favour of CEE which over-rides any negative information from other sources. After all, isn't this what most supplement sales are based on, i.e. people's claims and strong marketing? And we know from using them, that a lot of supplements really have very little positive effects. Yet supplements sell, and sell well. Could CEE in reality, fall into this category? Is CEE just a heavily marketed supplement fad?

Although CEE is probably not harmful in any way, it seems that it simply may not be as efficient as creatine monohydrate, and for sure it is no more efficient as creatine monohydrate. It therefore seems logical to save money and buy the type of creatine which is tried and tested: creatine monohydrate. My point is even if CEE formulas do work somewhat, they are certainly no better than monohydrate. And the outlandish claims that CEE gives 'no water retention' and such like are preposterous.


References:
  • ChemPharma Int'l. Final report of the study entitled "Identification and Quantitation of Bioavailable [14C] Compounds present it the Blood and Urine of Rats Following Oral Administration of a Single Dose of [14C] Creatine Ethyl Ester"
  • Child R, Tallon MJ 2004. Creatine ethyl ester rapidly degrades to creatinine in stomach acid 1Department of Life Sciences, Kingston University, Penrhyn Rd, Kingston-upon-Thames, United Kingdom. 2University of Northumbria, Sport Sciences, Northumbria University, Northumberland Building, Newcastle upon Tyne, United Kingdom, DrChild@CR-Technologies.net
  • FDA 2004: www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-rpt0249-01-vol181.pdf
  • MRI 2004: www.fda.gov/OHRMS/DOCKETS/dockets/95s0316/95s-0316-rpt0249-toc.htm

March 2010
Since this article was published it has attracted considerable attention. Although my findings above are quite negative about creatine ethyl ester, it is important to have balanced information. Please read the editorial from George C Summerfield, a lawyer representing the University of Nebraska, for the legal patent of CEE before writing it off as a performance enhancing supplement: The Rescue of Creatine Ethyl Ester