Toxicology Letters 152 (2004) 273274

Commentary

Writing about creatine: is it worth the risk?

Markus Wyss
DSM Nutritional Products, Biotech R & D, Building 203/17B, P.O. Box 3255, CH-4002 Basel, Switzerland
Received 4 May 2004
Available online 15 July 2004

Keywords: Creatine; Creatine metabolism; Creatine supplementation; Neuroprotection; Health benefits

Very recently, an interesting title of an article published in Toxicology Letters caught my attention:
Creatine: are the benefits worth the risk? (Brudnak,
2004). Because controversial opinions had been expressed in the past on the potential benefits and risks
of oral Cr supplementation, I expected an insightful,
critical discussion of these controversial opinions and
on their scientific basis. Disappointingly, however,
the article by Brudnak contains a number of errors,
of statements that lack a scientific basis, and of hypotheses for which a rationale is difficult to discern.
Overall, the reader not familiar with the field is misled
and confused, which certainly does not favor more
educated, qualified discussions in a field that has seen
rather emotional debates in the past.
The description of Cr biosynthesis and metabolism
(pp. 123125) is inconsistent in itself and in contradiction to general scientific knowledge. For a comprehensive overview, the reader is referred to Wyss
and Kaddurah-Daouk (2000). On page 125, Brudnak
states: . . . the amino-imidazo-azaarenes (AIA) [. . . ]
can be found in cooled fish, chicken, beef, pork, and
their extracts, implying that these mutagenic com-

Abbreviations: AIA, amino-imidazo-azaarene; Cr, creatine

Tel.: +41 61 688 2972; fax: +41 61 687 1847.
E-mail address: markus.wyss@dsm.com (M. Wyss).

pounds derived from Cr are inherently present in meat

and fish products. Very much to the contrary, however, AIAs are only formed at high temperatures, e.g.
during frying or broiling of meat, and also then at
concentrations so low that it is questionable whether
they represent any significant cancer risk. Similarly,
on page 128, it is stated that [. . . ] many pathogenic
organisms such as Pseudomonas, E. coli, yeast, etc.
process Cr to known mutagens such as the imidazoquinolines and imidazoquinoxalines. It is enigmatic
from which information this hypothesis is derived; no
corresponding report has been published so far.
Also the sentence . . . it is common to supplement
the diet with Cr at levels several hundred to often times
several thousand times the level naturally present in the
foods (p. 126) is misleading and might be interpreted
to imply an imponderable risk. However, the reality is
that the maximal recommended daily allowance of Cr
is 20 g (and most of the time, lower dosages are used
and/or recommended), that approximately one gram
per day of Cr is taken up through the diet, and that
approximately one gram per day of Cr is synthesized
de novo, primarily in the kidney, liver and pancreas
(Wyss and Kaddurah-Daouk, 2000).
On page 128, Brudnak outlines that Caffeine has
been reported anecdotally to have a negative effect
on the benefit derived from Cr supplementation. [. . . ]

0378-4274/$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.toxlet.2004.05.008

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M. Wyss / Toxicology Letters 152 (2004) 273274

most of the work demonstrating a positive effect for

Cr, used coffee as the delivery vehicle. Rather than
anecdotally, caffeine was shown in well-controlled scientific studies to negatively impact the ergogenic effects of oral Cr supplementation (Vandenberghe et al.,
1996; Hespel et al., 2002). In addition, even before the
adverse effects of concomitant caffeine intake were
known, water or fruit juices rather than coffee were
typically used as delivery vehicles for Cr.
By stating that [. . . ] Cr can reduce Huntingtin
plaque formation in Huntingtons Disease (p. 128),
Brudnak raises false expectations. While it is true that
Cr has shown beneficial effects in animal models of
Huntingtons disease, clinical studies have failed so far
to provide consistent neuroprotection in Huntingtons
disease patients (Kieburtz, 2001; Tabrizi et al., 2003;
Verbessem et al., 2003).
Also referencing of previous work was done incomprehensibly in Brudnak (2004): additionally, lactic
acid bacteria are known to reduce the mutagenicity and
carcinogenicity of Cr due to AIAs (Brudnak, 2001).
Last year one US pharmaceutical company alone produced over 5 million kilograms of creatine, with every batch assayed, and DHT never showed up on a
high-pressure liquid chromatography (HPLC) tracing
(Wyss and Kaddurah-Daouk, 2000). However, it was
observed that while torque was not affected, overall
relaxation time was with the co-ingestion of Cr and
caffeine (Brudnak, 2001). Indeed, it was found that
Cr can significantly [. . . ] attenuate blood glucose levels in diabetic mice (Blum et al., 2002). And Cr can
decrease the lesion size by up to 80% (Menalled and
Chesselet, 2002). In all these five examples, not the
least indication for any of the statements can be found
in the respective references!
With all these inconsistencies (and the list might be
further extended), it is somewhat surprising that Brudnak arrives at the conclusion that the (documented
and perceived) benefits of Cr are worth the (potential) risks, an opinion I entirely share with him. On
the other hand, for his article in question, it was in
hindsight not worth the risk for approaching the multifaceted fields of Cr supplementation in health and

disease and of Cr metabolism in general without appropriate scientific care. Brudnaks article shows, at
least and I seem to concur with him in this view ,
that there are still many open questions related to
Cr metabolism which are worth being analyzed in
detail, and which may have promising implications
for human well-being (see also Wyss and Schulze,
2002).

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