Possibili danni uso prolungato creatina
Chronic Creatine Use - Proceed With Caution?
August 28, 2000 by David Greenwalt CSCS About two years ago I made a recommendation for users of creatine monohydrate
supplements - "Cycle the use of creatine." There was really no great scientific foundation for making the recommendation. Creatine hadn't been shown to be toxic or even harmful to humans at the doses commonly used between 1993 and 1998. I made my recommendation for one reason - if any negative consequence of chronic creatine use was discovered I didn't want my customers to be in that camp. By cycling creatine monohydrate, as well as most dietary supplements, with the exception of a quality protein, multivitamin, and perhaps essential fats, I believed I was suggesting a more responsible method of supplementation. While I'm not disposing of my personal stash of creatine monohydrate I'm glad I followed my own advice and advised others to cycle creatine two years ago. A recent study published in Medical Hypotheses raises some potential concerns for chronic creatine users. Medical Hypotheses recently published the work of Dr. P.H. Yu titled "Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance" (1). The article is a mouse study, only three pages in length and is appropriately published in a "hypotheses" journal, however, the issues Dr. Yu raises are intriguing and ones I've never seen discussed before in relation to creatine supplementation. From my brief review of Dr. Yu's work spanning the past decade it appears Dr. Yu has a strong interest on the function and impairment of the endothelium (tissue lining blood vessels and cavities of the heart) and specifically the potential negative effects of formaldehyde on endothelial function. Why is it that diabetics suffer an increased risk of cardiovascular disease and atherosclerosis (hardening of the arteries) compared to healthy controls? Why do those suffering from renal (kidney) failure and dysfunction suffer increases in vascular problems? Dr. Yu's work continues to draw a link between a compound naturally produced in the body called methylamine and it's subsequent excessive conversion in the diseased states listed above to the endothelial toxin formaldehyde. How could this possibly relate to creatine monohydrate supplementation? That's the focus of the Medical Hypotheses study so bare with me. Yu writes "Creatine has been previously proposed to be converted by creatine aminohydrolase to urea and sarcosine, which would be further metabolized by glycine oxidase to glyoxalate and methylamine" (1). Methylamine has been detected in human urine, in blood and in tissues. It can be derived from several metabolic reactions, such as the deamination (removal of an amino group from a molecule) of adrenaline, sarcosine and creatinine, and it can probably be ingested from food and drinks. It is also synthesized endogenously (within the body) from choline and lecithin, adrenaline and can also be inhaled from cigarette smoke (2). Dr. Yu is not as concerned about the methylamine itself, as he is about how methylamine is metabolized to hydrogen peroxide and formaldehyde via an enzyme called semicarbazide-sensitive amine oxidase (SSAO). You may see where this is leading but in case you're as lost as I was the first time I read Yu's work I'll provide a synopsis of what I've said thus far. We know that repeated injury to endothelium has been implicated as an initiating factor for atherosclerosis. Dr. Yu believes that a naturally occurring, and relatively harmless compound called methylamine is converted to formaldehyde in excess by diabetics and those suffering kidney disease. However, he doesn't rule out potential problems for anyone increasing their endogenous methylamine production as this may increase the downstream metabolites such as formaldehyde, a known carcinogen, and hydrogen peroxide, a known free radical. The purpose of Yu's present work was to determine if creatine supplementation increased methylamine and formaldehyde in vivo, something never before addressed. To determine if creatine monohydrate supplementation increased the concentration of methylamine in vivo as well as formaldehyde he administered a single, oral dose of creatine to mice (50mg/kg) and measured urinary output of methylamine and formaldehyde. Remember that SSAO breaks methylamine down into formaldehyde and hydrogen peroxide. Dr. Yu didn't see an increase in urinary methylamine upon creatine administration, however, when he also administered creatine plus a SSAO inhibitor he did see a significant increase in urinary methylamine. But so what? By simply administering a SSAO inhibitor one would expect to find an increase in urinary methylamine because SSAO wouldn't be present break it down, thus it would pass out of the body still as methylamine. Yu found the SSAO inhibitor plus creatine increased urinary methylamine moreso than the SSAO inhibitor without creatine. This confirmed that creatine supplementation does increase methylamines in vivo. Further, the fact that no increase in urinary methylamines was observed with creatine supplementation absent the SSAO inhibitor suggests that under normal conditions additional methylamine created with creatine supplementation is metabolized by SSAO to end products prior to excretion from the body in urine. As I mentioned earlier, Yu isn't as concerned about increases in methylamine, however, he is very concerned about SSAO metabolizing methylamine to formaldehyde and hydrogen peroxide. "SSAO is located in the vascular smooth muscles and circulates in the blood. It is conceivable, therefore, that SSAO-mediated conversion of methylamine to formaldehyde occurs in the blood or vascular tissues. Vascular disorders could, therefore, be induced wherever SSAO is located" (3). So does in vivo production of formaldehyde increase in the presence of creatine supplementation. In this mouse study it appears the answer is yes. Dr. Yu was able to confirm via urine samples that "creatine caused a significant increase in urinary formaldehyde levels in comparison to controls" (1). Yu isn't making a pitch for creatine supplementation to end as we know it today, however, he does propose that "chronic administration of large quantities of creatine as a nutrition supplement would increase the production of methylamine and subsequently formaldehyde, which cross-links proteins and other molecules. This may be potentially cytotoxic, i.e., causing tissue damage in blood vessels in renal glomerula. A careful assessment of the chronic effect of creatine is needed" (1). To conclude, this mouse study needs replication in humans before we run for the hills away from creatine supplementation. The prudent approach to creatine supplementation is NOT to supplement if you have any pre-existing kidney disorder including uremia, as well as diabetes, or if you have any other medical condition and haven't spoken to your physician about creatine supplementation. And as always, never supplement with anything if you are pregnant or nursing without first consulting with your physician. If you have strong concerns about the safety of creatine use then don't supplement, however, for those who choose to continue to supplement with creatine monohydrate my advice is to cycle your supplementation with no longer than six week periods on and at least an equal time period off until further research into this area is completed. References: 1. P.H. Yu, Y. Deng, "Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance", Medical Hypotheses (2000) 54(5), 726-728 2. P.H. Yu, "Formaldehye produced endogenously via deamination of methylamine. A potential risk factor for initiation of endothelial injury." Atherosclerosis (1996) 120, 189-197 3. P.H. Yu, "Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase leads to cytotoxic damage in endothelial cells - Possible consequences for diabetes", Diabetes (1993)
August 28, 2000 by David Greenwalt CSCS About two years ago I made a recommendation for users of creatine monohydrate
supplements - "Cycle the use of creatine." There was really no great scientific foundation for making the recommendation. Creatine hadn't been shown to be toxic or even harmful to humans at the doses commonly used between 1993 and 1998. I made my recommendation for one reason - if any negative consequence of chronic creatine use was discovered I didn't want my customers to be in that camp. By cycling creatine monohydrate, as well as most dietary supplements, with the exception of a quality protein, multivitamin, and perhaps essential fats, I believed I was suggesting a more responsible method of supplementation. While I'm not disposing of my personal stash of creatine monohydrate I'm glad I followed my own advice and advised others to cycle creatine two years ago. A recent study published in Medical Hypotheses raises some potential concerns for chronic creatine users. Medical Hypotheses recently published the work of Dr. P.H. Yu titled "Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance" (1). The article is a mouse study, only three pages in length and is appropriately published in a "hypotheses" journal, however, the issues Dr. Yu raises are intriguing and ones I've never seen discussed before in relation to creatine supplementation. From my brief review of Dr. Yu's work spanning the past decade it appears Dr. Yu has a strong interest on the function and impairment of the endothelium (tissue lining blood vessels and cavities of the heart) and specifically the potential negative effects of formaldehyde on endothelial function. Why is it that diabetics suffer an increased risk of cardiovascular disease and atherosclerosis (hardening of the arteries) compared to healthy controls? Why do those suffering from renal (kidney) failure and dysfunction suffer increases in vascular problems? Dr. Yu's work continues to draw a link between a compound naturally produced in the body called methylamine and it's subsequent excessive conversion in the diseased states listed above to the endothelial toxin formaldehyde. How could this possibly relate to creatine monohydrate supplementation? That's the focus of the Medical Hypotheses study so bare with me. Yu writes "Creatine has been previously proposed to be converted by creatine aminohydrolase to urea and sarcosine, which would be further metabolized by glycine oxidase to glyoxalate and methylamine" (1). Methylamine has been detected in human urine, in blood and in tissues. It can be derived from several metabolic reactions, such as the deamination (removal of an amino group from a molecule) of adrenaline, sarcosine and creatinine, and it can probably be ingested from food and drinks. It is also synthesized endogenously (within the body) from choline and lecithin, adrenaline and can also be inhaled from cigarette smoke (2). Dr. Yu is not as concerned about the methylamine itself, as he is about how methylamine is metabolized to hydrogen peroxide and formaldehyde via an enzyme called semicarbazide-sensitive amine oxidase (SSAO). You may see where this is leading but in case you're as lost as I was the first time I read Yu's work I'll provide a synopsis of what I've said thus far. We know that repeated injury to endothelium has been implicated as an initiating factor for atherosclerosis. Dr. Yu believes that a naturally occurring, and relatively harmless compound called methylamine is converted to formaldehyde in excess by diabetics and those suffering kidney disease. However, he doesn't rule out potential problems for anyone increasing their endogenous methylamine production as this may increase the downstream metabolites such as formaldehyde, a known carcinogen, and hydrogen peroxide, a known free radical. The purpose of Yu's present work was to determine if creatine supplementation increased methylamine and formaldehyde in vivo, something never before addressed. To determine if creatine monohydrate supplementation increased the concentration of methylamine in vivo as well as formaldehyde he administered a single, oral dose of creatine to mice (50mg/kg) and measured urinary output of methylamine and formaldehyde. Remember that SSAO breaks methylamine down into formaldehyde and hydrogen peroxide. Dr. Yu didn't see an increase in urinary methylamine upon creatine administration, however, when he also administered creatine plus a SSAO inhibitor he did see a significant increase in urinary methylamine. But so what? By simply administering a SSAO inhibitor one would expect to find an increase in urinary methylamine because SSAO wouldn't be present break it down, thus it would pass out of the body still as methylamine. Yu found the SSAO inhibitor plus creatine increased urinary methylamine moreso than the SSAO inhibitor without creatine. This confirmed that creatine supplementation does increase methylamines in vivo. Further, the fact that no increase in urinary methylamines was observed with creatine supplementation absent the SSAO inhibitor suggests that under normal conditions additional methylamine created with creatine supplementation is metabolized by SSAO to end products prior to excretion from the body in urine. As I mentioned earlier, Yu isn't as concerned about increases in methylamine, however, he is very concerned about SSAO metabolizing methylamine to formaldehyde and hydrogen peroxide. "SSAO is located in the vascular smooth muscles and circulates in the blood. It is conceivable, therefore, that SSAO-mediated conversion of methylamine to formaldehyde occurs in the blood or vascular tissues. Vascular disorders could, therefore, be induced wherever SSAO is located" (3). So does in vivo production of formaldehyde increase in the presence of creatine supplementation. In this mouse study it appears the answer is yes. Dr. Yu was able to confirm via urine samples that "creatine caused a significant increase in urinary formaldehyde levels in comparison to controls" (1). Yu isn't making a pitch for creatine supplementation to end as we know it today, however, he does propose that "chronic administration of large quantities of creatine as a nutrition supplement would increase the production of methylamine and subsequently formaldehyde, which cross-links proteins and other molecules. This may be potentially cytotoxic, i.e., causing tissue damage in blood vessels in renal glomerula. A careful assessment of the chronic effect of creatine is needed" (1). To conclude, this mouse study needs replication in humans before we run for the hills away from creatine supplementation. The prudent approach to creatine supplementation is NOT to supplement if you have any pre-existing kidney disorder including uremia, as well as diabetes, or if you have any other medical condition and haven't spoken to your physician about creatine supplementation. And as always, never supplement with anything if you are pregnant or nursing without first consulting with your physician. If you have strong concerns about the safety of creatine use then don't supplement, however, for those who choose to continue to supplement with creatine monohydrate my advice is to cycle your supplementation with no longer than six week periods on and at least an equal time period off until further research into this area is completed. References: 1. P.H. Yu, Y. Deng, "Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance", Medical Hypotheses (2000) 54(5), 726-728 2. P.H. Yu, "Formaldehye produced endogenously via deamination of methylamine. A potential risk factor for initiation of endothelial injury." Atherosclerosis (1996) 120, 189-197 3. P.H. Yu, "Oxidative deamination of methylamine by semicarbazide-sensitive amine oxidase leads to cytotoxic damage in endothelial cells - Possible consequences for diabetes", Diabetes (1993)
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