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Carnitine Study: A Response, April 2013

You may have heard or read about carnitine — found in red meat or taken as a supplement — possibly being a risk factor for heart disease. I also know that many of you are taking dietary supplements containing carnitine, often in combination with lipoic acid. This combination, as well as carnitine taken alone, is known to increase fat burning and improve energy metabolism, especially in older adults.

But according to the study, a metabolite of carnitine called trimethylamine oxide (TMAO) is formed by gut bacteria (intestinal microbiota) and absorbed into the body. High plasma levels of carnitine in human subjects were found to be associated with an increased risk of cardiovascular disease, including heart attack and stroke. Furthermore, in a mouse model TMAO enhanced cholesterol absorption and altered cholesterol metabolism in the liver and in monocyte-macrophages (inflammatory white blood cells), thereby promoting atherosclerosis (the underlying cause of cardiovascular disease)

The original paper was published in the prestigious scientific journal, Nature Medicine. The principal investigator and senior author of the study is Dr. Stanley Hazen, a highly respected and first-rate scientist.

My immediate reaction to the study is that it is intriguing and novel, but far from definitive. I certainly wouldn't draw any conclusions at this point with respect to heart disease risk in humans. The possible culprit, TMAO, comes also from many other sources besides carnitine, such as choline, choline phospholipids, acetyl choline, and even fish, which we know lowers cardiovascular risk. Moreover, plasma levels of trimethyllysine, which is the immediate precursor of TMAO, can be naturally quite high in humans, but are little affected by carnitine supplementation. Interestingly enough, while carnitine levels were associated with an increased risk of cardiovascular disease in the study, TMAO itself was not. Only after some statistical manipulations did the authors find an association between increased heart disease risk and increased levels of carnitine and TMAO combined.

It is possible that carnitine and TMAO levels in humans are "only" a marker of red meat intake rather than a causative agent in heart disease. Just because carnitine levels are associated with increased heart disease risk does not mean carnitine (or TMAO) causes heart disease in humans. Correlation is not necessarily causation. Much more work needs to be done to establish mechanisms and causality in humans. To call it a culprit in heart disease (as the press labeled it) is premature. The main culprit in red meat is saturated fat, and I don't think carnitine or TMAO will get even close to saturated fat in terms of causing atherosclerosis and increasing cardiovascular risk in humans. Relative risk is important, and we know the major coronary risk factors in humans.

Right now, we have a large body of work that has accumulated over decades that acetyl-l-carnitine and lipoic acid are safe to use at appropriate doses. Acetyl-l-carnitine alone has been given clinically at very high doses (as much as 8 grams per day) with no observed side effects, including those suggested by this study. We know that acetyl-l-carnitine improves mitochondrial function, lowers lipid levels (which would lower cardiovascular risk), and improves muscle function and cognition. So, I think that carnitine has strong health benefits, and this "risk-to-benefit ratio" needs to be taken into account. Right now, this new study is the only one that suggests there may also be an adverse effect in some individuals with the use of carnitine as a precursor of TMAO. Based on current evidence, I believe that the balance favors the use of carnitine supplements (perhaps without simultaneous high levels of red meat consumption). However, we must prudently and continually reassess our recommendations based on new scientific information, and that is what we will do in this instance.

For now, I continue to take my combined lipoic acid and carnitine supplement and will also continue to monitor my heart disease risk — which is very low as I have a highly favorable lipid profile (low total and LDL cholesterol, high HDL cholesterol, low triglycerides), normal blood pressure, normal blood glucose, healthy body weight and waist circumference, and low inflammation (plasma CRP levels); in addition, I exercise regularly — and avoid red meat!

More information on carnitine can be found on the Linus Pauling Institute Micronutrient Information Center.

Balz Frei, PhD
Distinguished Professor of Biochemistry and Biophysics
Director and Endowed Chair
Linus Pauling Institute
Oregon State University