Meldonium vs L-carnitine: what is the difference
Meldonium and L-carnitine are often mentioned together as agents «for energy and the heart». The paradox is that meldonium is aimed at lowering carnitine levels, while L-carnitine is aimed at replenishing them. The editorial team explains how two substances can be linked to one metabolic pathway and at the same time act in opposite directions.
Carnitine: where it all begins
Carnitine is a small molecule that transports long-chain fatty acids into the mitochondria, where they are oxidised to produce energy. Without carnitine fatty acids cannot get into the cell's «furnace». About 95% of the body's carnitine stores are concentrated in skeletal muscle.
A person obtains carnitine in two ways: from food, primarily red meat and dairy products, and through its own synthesis in the liver and kidneys from the amino acids lysine and methionine. The last step of synthesis is the conversion of gamma-butyrobetaine to carnitine by the enzyme gamma-butyrobetaine hydroxylase.
Carnitine enters muscle cells with the help of a special transporter, OCTN2, which works against a concentration gradient. The kidneys efficiently reabsorb carnitine, so in a healthy person its level in the blood is maintained quite steadily, even in vegetarians, although in them it is somewhat lower.
The review by Stephens, Constantin-Teodosiu and Greenhaff (2007) showed another role of carnitine: during intense exercise it binds excess acetyl groups, forming acetylcarnitine. This helps maintain the activity of the enzyme pyruvate dehydrogenase and, accordingly, the oxidation of carbohydrates.
How meldonium acts
Meldonium (mildronate) was developed in Latvia in the 1970s. In structure it is a structural analogue of gamma-butyrobetaine. Because of this it inhibits the enzyme gamma-butyrobetaine hydroxylase - that is, the last step of carnitine synthesis - and competes with carnitine for the OCTN2 transporter, increasing its excretion by the kidneys.
As a result, the level of carnitine in tissues, in particular in the heart, decreases. According to the developers' concept, this limits the oxidation of fatty acids and forces the cell to use more glucose, which requires less oxygen per unit of energy produced. This effect is argued for conditions of ischemia, when oxygen is lacking.
The review by Dambrova and co-authors (2016) also describes other potential effects of meldonium: accumulation of gamma-butyrobetaine, an effect on nitric oxide and cardiometabolic markers. Most of the mechanistic data was obtained in experimental models, and clinical studies were carried out mainly in the countries of the former USSR.
So meldonium is a metabolic modulator that affects the ratio of the cell's «fuel» pathways through lowering carnitine. This is precisely what both the claimed medical uses and the interest in it in sport are based on.
How the L-carnitine supplement works
L-carnitine in supplement form (usually L-carnitine tartrate, acetyl-L-carnitine or the free base) is the same molecule that is formed in the body. The idea of the supplement is simple: to increase the availability of carnitine and, in theory, enhance the transport of fatty acids into the mitochondria.
The problem is that there is already enough carnitine in the muscles, and its uptake by the OCTN2 transporter is limited. The oral bioavailability of the supplement is also low. For years studies could not show that taking L-carnitine increases its content in muscle.
The situation was changed by the work of Wall and co-authors (J Physiol, 2011). Participants took L-carnitine together with a large amount of carbohydrates twice a day for 24 weeks. Insulin stimulated the uptake of carnitine by the muscles, and their carnitine content increased by about a fifth. Without carbohydrates there was no such effect. This explains why short courses of the supplement without carbohydrates have almost no effect.
A separate line is the effect of L-carnitine tartrate on recovery after exercise. A number of studies described a reduction in markers of muscle damage and soreness, and these data are summarised in the review by Fielding and co-authors (2018). However, the effects are moderate, and the quality of the studies varies.
| Parameter | Meldonium | L-carnitine |
|---|---|---|
| Direction of effect on carnitine | Lowers the tissue level | Replenishes (under certain conditions) |
| Target | Synthesis enzyme, OCTN2 transporter | Substrate for the transport of fatty acids |
| Fuel shift (concept) | From fats to glucose | Support of fat oxidation |
| Status | A medicinal product in a number of countries; banned by WADA | A dietary supplement, permitted |
Status, anti-doping rules and evidence base
Meldonium is registered as a medicinal product in Latvia, Ukraine and a number of other post-Soviet countries, mainly for use in ischemic heart disease and disorders of cerebral circulation. It is not approved by the FDA in the USA and has no centralised registration in the EU. There are few large independent randomised studies of it by international standards.
From 1 January 2016 meldonium was added to the WADA Prohibited List in the class of hormonal and metabolic modulators; it is banned at all times - both in and out of competition. The decision was preceded by the study of Görgens and co-authors (2015), which detected meldonium in about 2% of the analysed doping samples of athletes, indicating its widespread use.
In 2016, after inclusion in the list, there were more than a hundred positive tests, including among well-known athletes. Some cases were linked to the fact that the substance had been taken before the ban and was excreted longer than expected. This underlines that the elimination period of meldonium is long.
L-carnitine is not banned by WADA as a supplement. At the same time, intravenous infusions of any substances above the volume set in the Prohibited List over a certain period are among the prohibited methods, unless they are carried out as part of treatment in hospital or in clinical trials. Athletes should take this rule into account.
Safety and risks
Meldonium as a medicinal product has a patient leaflet with a list of adverse reactions, among them allergic reactions, digestive upset, tachycardia, changes in blood pressure and agitation. The editorial team does not support self-administration without indications, especially in sport - both because of the uncertainty of the benefit-to-risk ratio and because of the anti-doping consequences.
L-carnitine is generally well tolerated. At high doses nausea, diarrhoea and a specific «fishy» body odour linked to the formation of trimethylamine are possible. The work of Koeth and co-authors (Nat Med, 2013) is discussed separately: the gut microbiota converts carnitine to TMAO - a metabolite associated with atherosclerosis in animal models and observational studies.
The significance of TMAO for people who take carnitine has not been definitively established: this is an association, not a proven cause-and-effect relationship. However, people with cardiovascular diseases should discuss long-term use of the supplement with a doctor.
- Meldonium:a prescription agent in a number of countries, banned by WADA, with a long elimination period.
- L-carnitine:a supplement with a good safety profile, with possible gastrointestinal effects and questions around TMAO.
- Both:do not have convincing evidence of improving athletic performance in healthy people.
Editorial conclusions
Meldonium and L-carnitine are linked to one and the same metabolic pathway but move it in opposite directions: meldonium lowers the carnitine level and shifts energy metabolism towards glucose, while the carnitine supplement replenishes it, though in muscle - only under certain conditions.
The status also differs: meldonium is a medicinal product with a limited international evidence base and banned by WADA, while L-carnitine is a permitted supplement with moderate and not always reproducible effects.
Who should consider what and when, we cover in the article «Meldonium vs L-carnitine: what to choose and for whom». We also recommend the editorial pieces on the WADA Prohibited List, on acetyl-L-carnitine and on creatine and beta-alanine.
References
- Dambrova M, Makrecka-Kuka M, Vilskersts R, et al. Pharmacological effects of meldonium: biochemical mechanisms and biomarkers of cardiometabolic activity. Pharmacol Res. 2016;113(Pt B):771–780.
- Görgens C, Guddat S, Dib J, et al. Mildronate (Meldonium) in professional sports — monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry. Drug Test Anal. 2015;7(11–12):973–979.
- World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List 2016. Montreal: WADA; 2015.
- Stephens FB, Constantin-Teodosiu D, Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol. 2007;581(Pt 2):431–444.
- Wall BT, Stephens FB, Constantin-Teodosiu D, et al. Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans. J Physiol. 2011;589(Pt 4):963–973.
- Fielding R, Riede L, Lugo JP, Bellamine A. L-Carnitine supplementation in recovery after exercise. Nutrients. 2018;10(3):349.
- Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–585.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
