By Steve Blechman

New Studies Says:  

The most up-to-date review on the dietary supplement L-carnitine and exercise performance was recently published in the January 1^st issue of the journal Molecules. There is controversy as to whether carnitine supplementation can improve exercise performance. “Despite many years of research on the role of carnitine in muscle metabolism, it is yet not completely established whether carnitine supplementation can improve physical performance in healthy subjects,” the researchers said.  

“The discrepancies in published research could be related to the features of carnitine pharmacokinetic. First, it must be considered that when orally furnished, carnitine bioavailability is only 5-15%,” the researchers noted.

“In fact, after an acute administration of a large amount of carnitine, most of the carnitine is recovered in the urine,” the researchers said. Therefore, high doses of carnitine are required to increase muscle carnitine. For example, the researchers cite that 6 grams of carnitine taken over a couple of weeks in healthy males did not affect vO₂ max or exercise performance. A recent study in vegetarians with low muscle carnitine levels found that 2 grams of carnitine did not increase muscle function or energy metabolism.

“Based on these considerations, it is conceivable to predict that oral carnitine supplementation would have little if any effect on muscle carnitine content in humans, and thus on muscle metabolism. Indeed, studies have demonstrated that even if long-term carnitine administration in humans increases plasma carnitine concentrations, it does not increase muscle carnitine content,” the researchers noted. It has been reported in the scientific literature that high circulating insulin levels can increase carnitine in muscle.

In conclusion, the researchers state, “Theoretically, carnitine supplementation should increase carnitine muscle content, thus improving fatty acid oxidation and exercise function in healthy humans. However, so far, no scientific basis supports improvement in exercise performance for healthy individuals or athletes after carnitine supplementation. Moreover, considering that carnitine metabolism produces TMAO, which has been recently recognized as a novel risk factor for cardiovascular diseases, the use of uncontrolled amounts of carnitine as supplements must be carefully reviewed.” 

“Since carnitine is often used by athletes with no clear understanding of its effects and risks, it becomes critical to provide information about the characteristics of this compound and its probable harmful effects on health,” the researchers said. “With the adoption of educational approaches, it will be possible to reduce the risk associated with dietary and nutritional carnitine supplementation, in particular among athletes.”

Another most recent study published in the February 5^th International Journal of Molecular Science found that carnitine supplementation may increase the risk of cardiovascular disease by a new mechanism of action by the increase and impairment of methyl-metabolism by TMAO. This study followed women for 6 months on L-carnitine supplementation combined with exercise or exercise alone.  The study included three groups: one group taking 4,000mg of L-leucine alone per day or leucine (3000mg) combined with carnitine (1000mg) with resistance training and resistance training alone and measuring TMAO. Only carnitine supplements increased TMAO blood levels. Trimethylamine-N-oxide (TMAO) increased after 6 months in the women that consumed L-carnitine with regular physical exercise. Like I said earlier, no significant effect of TMAO was found in the group of women training alone without L-carnitine supplements. TMAO levels after 6 months of carnitine supplementation were associated with higher low-density lipoprotein cholesterol (LDLC) and total cholesterol. Research has shown that higher LDL cholesterol (bad cholesterol) is a strong independent risk factor for cardiovascular disease in humans. “The evidence supports the hypothesis that the correlation between L-carnitine and atherosclerosis might be more complex than already postulated and the alteration of mitochondrial DNA (mtDNA) methylation in platelets could be involved in the pathogenesis of this multi-factorial disease,” researchers noted. This was a small sample-sized study, and larger randomized controlled studies are needed to confirm this new possible mechanism of action involving carnitine supplements and increased risk of cardiovascular disease. 

Two other studies published in the Journal of Clinical Investigation (Dec. 10, 2018) and the European Heart Journal (Dec. 10, 2018) showed that red meat and carnitine supplements may increase the risk for heart disease! The study in the European Heart Journal involved 113 healthy men and women to determine the effect of consuming red meat and white meat (such as chicken or turkey) on TMAO levels. All the subjects were on the diet for a month. After a month, TMAO levels for red meat eaters tripled compared to those consuming white meat or non-meat protein sources. Nutrition experts recommend reducing intake of red meat in the diet because it is high in saturated fat, which promotes coronary artery disease. A Cleveland Clinic study led by Stanley Hazen found that carnitine, a popular athletic supplement and component of red meat, may also trigger heart disease. Bacteria in the gut break down carnitine to trimethylamine N-oxide (TMAO), which can promote arterial disease by increasing cholesterol deposits in the arteries and inflammation. High TMAO in the blood can cause abnormal blood clots and is a good predictor of heart attack and stroke.

Thirty-seven years ago, in 1983, I was the first to introduce and bring L-carnitine to America from Japan as a supplement during my 27 years as Head of Product Development at Twinlab (1974-2001). Today L-carnitine is an extremely popular supplement. I have ceased taking L-carnitine as a dietary supplement for many years because of the lack research supporting L-carnitine for weight loss, fat loss, exercise performance and of course the concern of TMAO and its involvement in cardiovascular disease risk. L-carnitine is an important chemical found in mitochondria – the cells’ energy centers – where it helps break down long-chain fatty acids and promotes oxygen consumption. A study published in the International Journal of Sports Nutrition and Exercise Metabolism showed that L-carnitine supplementation combined with aerobic training does not promote weight loss. Another study published in the Scandinavian Journal of Medicine & Science in Sports in 2018 found that increasing muscle carnitine during 24 weeks of HIIT (high-intensity interval training) did not enhance muscle metabolic adaptations or performance gains beyond those with HIIT alone. An Iranian meta-analysis (combination of many studies) showed that supplementing L-carnitine had no effect on physical performance.

Another study published in the Journal of Clinical Investigation acknowledged that L-carnitine has been shown to accelerate atherosclerosis in mice by the formation of TMAO in the GI tract. What’s most concerning in the Journal of Clinical Investigation study was that L-carnitine supplementation, even among vegan/vegetarians, has an effect on gut microbiota and can increase TMAO. It is clear from this study that chronic L-carnitine supplementation stimulates TMAO concentrations in humans

Research has shown that red meat has raised the risk of heart disease and colon cancer. It was reported on NBC News by Maggie Fox: “Hazen’s team showed gut bacteria convert an amino acid called carnitine into TMAO. When they gave carnitine supplements to meat eaters, their gut bacteria quickly started making TMAO. At first the bodies of vegetarians and vegans did not produce much TMAO even when they took supplements, but after a few weeks they did, Hazen’s team reported in the Journal of Clinical Investigation.”

In Medical Express on December 10, 2018 it was reported, “The findings suggest that measuring and targeting TMAO levels – something doctors can do with a simple blood test – may be a promising new strategy for individualizing diets and helping to prevent heart disease. The study was funded largely by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.” It was published December 10, 2018 in the European Heart Journal.

“This study shows for the first time what a dramatic effect changing your diet has on levels of TMAO, which is increasingly linked to heart disease,” said Stanley L. Hazen, MD, Ph.D., senior author of the study and section head of Preventive Cardiology & Rehabilitation at the Cleveland Clinic. “It suggests that you can lower your heart disease risk by lowering TMAO.”

Unfortunately, supplementation with L-carnitine has been shown to have no influence on fat loss when consumed alone. L-carnitine functions by transporting fatty acids into the mitochondrion, where they are burned for energy. Even though L-carnitine’s central role is enhancing fatty acid oxidation, L-carnitine has been shown to have no influence on fat burning or fat loss when consumed alone. In fact, a study in the American Journal of Clinical Nutrition, 2016, showed that when L-carnitine is consumed with whey protein, whey protein inhibited the uptake of L-carnitine. The combined use of whey protein to increase L-carnitine levels for fat loss is ineffective and therefore, not recommended. As recently as March 2018, it was reported in the International Journal of Sports Nutrition and Exercise Metabolism that, “It is likely that the lack of efficacy in many studies is due to its low bioavailability and failure to increase muscle L-carnitine stores.”

References:

1. Gnoni A, Longo S, Gnoni GV, Giudetti AM. Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise? Molecules. 2020;25(1):182. Published 2020 Jan 1. doi:10.3390/molecules25010182

2. Bordoni, L.; Sawicka, A.K.; Szarmach, A.; Winklewski, P.J.; Olek, R.A.; Gabbianelli, R. A Pilot Study on the Effects of l-Carnitine and Trimethylamine-N-Oxide on Platelet Mitochondrial DNA Methylation and CVD Biomarkers in Aged Women. Int. J. Mol. Sci.2020, 21, 1047. 

3. Broderick T.L., Quinney H.A., Lopaschuk G.D. Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J. Biol. Chem. 1992;267:3758–3763

4. Vukovich M.D., Costill D.L., Fink W.J. Carnitine supplementation: Effect on muscle carnitine and glycogen content during exercise. Med. Sci. Sports Exerc. 1994;26:1122–1129. doi: 10.1249/00005768-199409000-00009. 

5. Oyono-Enguelle S., Freund H., Ott C., Gartner M., Heitz A., Marbach J., Maccari F., Frey A., Bigot H., Bach A.C. Prolonged submaximal exercise and l-carnitine in humans. Eur. J. Appl. Physiol. Occup. Physiol. 1988;58:53–61. doi: 10.1007/BF00636603. 

6. Soop M., Björkman O., Cederblad G., Hagenfeldt L., Wahren J. Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise. J. Appl. Physiol. 1988;64:2394-2399. doi: 10.1152/jappl.1988.64.6.2394.

7. Brass E.P., Hoppel C.L., Hiatt W.R. Effect of intravenous l-carnitine on carnitine homeostasis and fuel metabolism during exercise in humans. Clin. Pharmacol. Ther. 1994;55:681-692. doi: 10.1038/clpt.1994.85 

8. Novakova K., Kummer O., Bouitbir J., Stoffel S.D., Hoerler-Koerner U., Bodmer M., Roberts P., Urwyler A., Ehrsam R., Krähenbühl S. Effect of l-carnitine supplementation on the body carnitine pool, skeletal muscle energy metabolism and physical performance in male vegetarians. Eur. J. Nutr. 2016;55:207-217. doi: 10.1007/s00394-015-0838-9. 

9. Harper P., Elwin C.E., Cederblad G. Pharmacokinetics of intravenous and oral bolus doses of l-carnitine in healthy subjects. Eur. J. Clin. Pharmacol. 1988;35:555–562. doi: 10.1007/BF00558253.

10. Evans A.M., Fornasini G. Pharmacokinetics of L-carnitine. Clin. Pharmacokinet. 2003;42:941-967. doi: 10.2165/00003088-200342110-00002. 

11. Randrianarisoa E., Lehn-Stefan A., Wang X., Hoene M., Peter A., Heinzmann S.S., Zhao X., Königsrainer I., Königsrainer A., Balletshofer B., et al. Relationship of serum Trimethylamine N-Oxide (TMAO) levels with early atherosclerosis in humans. Sci. Rep. 2016;6:26745. doi: 10.1038/srep26745. 

12. Tang W.H., Hazen S.L. Microbiome, Trimethylamine N-Oxide (TMAO), and cardiometabolic disease. Transl. Res. 2017;179:108-115. doi: 10.1016/j.trsl.2016.07.007. 

13. Ding L., Chang M., Guo Y., Zhang L., Xue C., Yanagita T., Zhang T., Wang Y. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis. 2018;17:286. doi: 10.1186/s12944-018-0939-6. 

14. Arsenian M.A. Carnitine and its derivatives in cardiovascular disease. Prog. Cardiovasc. Dis. 1997;40:265–286. doi: 10.1016/S0033-0620(97)80037-0. 

15. Koeth R.A., Lam-Galvez B.R., Kirsop J., Wang Z., Levison B.S., Gu X., Copeland M.F., Bartlett D., Cody D.B., Dai H.J., et al. L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J. Clin. Investig. 2019;129:373–387. doi: 10.1172/JCI94601 

16. Wu W.K., Chen C.C., Liu P.Y., Panyod S., Liao B.Y., Chen P.C., Kao H.L., Kuo H.C., Kuo C.H., Chiu T.H.T., et al. Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Gut. 2019;68:1439-1449. doi: 10.1136/gutjnl-2018-317155.

17. Gao X., Tian Y., Randell E., Zhou H., Sun G. Unfavorable associations between serum trimethylamine N-oxide and l-carnitine levels with components of metabolic syndrome in the Newfoundland population. Front. Endocrinol. 2019;10:168. doi: 10.3389/fendo.2019.00168.

18. L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. SL.Hazen et al Published December 10, 2018 J Clin Invest 2018. https://doi.org/10.1172/JCI94601 

19. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women, European Heart Journal, SL Hazen et al; https://doi.org/10.1093/eurheartj/ehy799 

20. Increasing skeletal muscle carnitine availability does not alter the adaptations to high-intensity interval training. Christopher E. Shannon, et al. Scand J Med Sci Sports 2018;28: 107-115.

21. Protein ingestion acutely inhibits insulin-stimulated muscle carnitine uptake in healthy young men. Shannon CE, Nixon AV, et al. Am J Clin Nutr 2016.

22. Study explains how red meat raises heart disease risk. Eating meat also altered kidney function, the researchers found. Maggie Fox, NBC News, December 10, 2018 https://www.nbcnews.com/health/health-news/study-explains-how-red-meat-raises-heart-disease-risk-n946241

23. Protein ingestion acutely inhibits insulin-stimulated muscle carnitine uptake in healthy young men. Shannon CE, Nixon AV, et al. Am J Clin Nutr 2016.

24. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. SL Hazen et al. New England Journal of Medicine, 368: 1575-1584 https://www.nejm.org/doi/full/10.1056/NEJMoa1109400 

25. Zhu W, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016;165(1):111-124. 

26. Janeiro, M.H., Ramírez, M.J., Milagro, F.I., Martínez, J.A., & Solas, M. (2018). Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target. Nutrients 10(10), 1398. doi:10.3390/nu10101398 

27. Study links frequent red meat consumption to high levels of chemical associated with heart disease, Medical Express, December 11, 2018, NIH/National Heart, Lung and Blood Institute https://medicalxpress.com/news/2018-12-links-frequent-red-meat-consumption.html

28. L-carnitine supplementation combined with aerobic training does not promote weight loss in moderately obese women. Villani RG, Gannon J, et al. Int. J Sport Nutr Exerc Metab, 2000; 10, 199-207. 

29. Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans. Wall BT, Stephens FB, et al. J Physiol 2011; 589, 963-973.

30. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Manuel T Velasquez, et al. Toxins (Basel). 2016 Nov; 8(11): 326.