Creatine Ethyl Ester: Leave it on the shelf

Creatine monohydrate has a large and growing body of literature to support not only its performance enhancing effects, but also its therapeutic effects in many diseases (muscular dystrophy, parkinsons). Despite this, it has been estimated that as few as 20% of users actually saturate their creatine stores when supplementing and as many as 30% fail to respond at all (1). While we don’t have a precise explanation for the variable response to creatine supplementation, one theory suggests that creatine uptake is the limiting factor in non-responders. As a consequence, current research has focused on modifying creatine in order to improve uptake and hopefully improve performance in non-responders.

Without hitting the chemistry too hard, creatine is a polar molecule that is hydrophilic (water-loving), which limits its ability to freely enter muscle cells by passing through the cell membrane (sarcolemma). Because cell membranes have a hydrophobic (water-phobic) core, creatine requires a specific transporter to cross the cell membrane. The fact that creatine requires a transporter system could limit its ability to enter the target cell, in this case muscle, which can limit creatine loading. There are various ways to modify compounds that can alter their behaviour in solution, and ultimately allow them to freely cross the cell membrane and increase uptake, overcoming the potential transport barrier. So in the case of creatine ethyl ester (CEE), an ethyl ester was linked to creatine in the hopes that this could bypass the transporter system and improve creatine uptake compared to the ‘old’ monohydrate form.

Problem is, what works in theory or in a petri dish doesn’t always correspond to the desired effect when you look at the systems level (ie: an actual human). In this case, creatine ethyl ester has to take a winding journey through the digestive tract and along the way encounter various pH solutions before arriving in your bloodstream and ultimately into your muscle. Unfortunately, recent data indicates that CEE rapidly converts to the by-product of creatine metabolism, Creatinine, under various pH conditions similar to what is found along your digestive tract and the path to your muscle (2,3). Simply stated, the chemical modifications we expected to increase creatine uptake, actually resulted in the conversion of CEE to creatinine and NOT usable creatine.

So couple that with a batch of studies showing that CEE fails to increase serum muscle creatine (4), is less effective at increasing muscle creatine content (4), non-enzymatically degrades to creatinine in solution (2,3) and elevates serum creatinine when ingested (4,5) and you’ll be left with the sinking feeling you’ve flushed your hard-earned dollars down the drain. Irrespective of the potential advantageous creatine loading effect (which didn’t pan out), the simple fact that CEE can promote increased creatinine, while monohydrate does not, is justification enough to leave it on the shelf (4).

In the end, the idea behind creatine ethyl ester may not have been some plot to increase profits at an evil supplement company, there are actually legitimate needs for this product outside of athletic performance. Take for example individuals that have a creatine transporter deficiency, which can cause significant impairment of brain function (6). If we can design a form of creatine that can bypass the transporter, then there could be substantial therapeutic potential for these people. And while preliminary data looked promising, at least for CEE uptake in cell culture (6), creatine was not elevated in brain tissue in these patients following one year of supplementation. So as it stands right now, at least for the performance-minded individual, the evidence suggests you’ll be better off spending your money on creatine monohydrate.


    Awesome! Were you at the last ISSN meeting in Vegas? I was there presenting and hanging out—awesome time! Dr. Roger Harris presented and was on a panel discussing creatine and stated that we were pretty lucky that CEE just turned out to be ineffective and not dangerous; as it could've been really bad.

    Keep up the research based approach!!
    rock on
    Mike T Nelson PhD(c)

    dan_ogborn says:

    Unfortunately I couldn't make ISSN, wish I could have. Definitely a good thing CEE didn't block creatine metabolism as was feared initially, although that would have likely got it off the market faster. Thanks for checking out the site, I've been enjoying yours for awhile now.

    Bono says:

    Ya learn something new everdyay. It's true I guess!

    ally says:

    Hey Dan- great article. I know that many women who weight train are still hesitant about using Creatine Monohydrate, and rather opt for CEE with its promises to not fluctuate weight/cause bloating (whether true or not). Are there any reasons for women to not use CM, particularly those with a more endomorphic bodytype rather that ecto/meso? Will it do all that CEE aims to do, but with some potential negative effects? I would really be interested to read your opinion, as i have looked at the studies and i still am unable to make my mind up about using CM!

    Thank you, Ally (bikini competitor) x

    Dan Ogborn says:

    Hi Ally,

    Given the problems with CEE, I wouldn’t bother with it even if the bloating claims were true. The increased total body water with CM probably has a greater impact on muscle than other tissues, and any swelling from increased water content, in my opinion, would likely enhance the appearance of the muscle rather than impair it. If I were working with individuals in the situation you described I would 1) never bother with CEE, 2) use CM and 3) if they felt strongly that it negatively impacted performance, appearance or couldn’t tolerate it (GI) discontinue use.

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Dan Ogborn