Mildronate (Meldonium) - The Strongest Performance Enhancer You’ve Never Heard Of
If you follow the Olympics, or any other international sporting events, you may have heard of a magical compound that can give unlimited energy for performance. It’s so good, in fact, that in 2016 over 170 athletes tested positive for it. This included tennis phenom Maria Sharapova. 
This article will go into depth on the chemistry, mechanism of action, and safety of the wunderdrug known as meldonium - or mildronate.
Related - The Power of Nitrates - Gym Performance & Muscle Enhancement
A Look at Mildronate
Meldonium, manufactured exclusively in Eastern Europe under the brand name Mildronate, is a partial inhibitor of fatty acid oxidation via competitively inhibiting the enzyme gamma-butyrobetaine hydroxylase. This enzyme is necessary for the synthesis of carnitine from its precursor gamma-butyrobetaine.
Mildronate, not approved in the US, is prescribed to help treat coronary artery disease and as an anti-ischemia agent. Ischemia is a condition where there is not enough blood flow to your body’s major organs, including your heart. When inhibiting carnitine synthesis, meldonium induced vasodilation of your coronary arteries by increasing nitric oxide production and oxidation of glucose, thus reducing blood glucose concentrations.
Meldonium is also said to have cardioprotective properties via inhibiting the biosynthesis of carnitine. Beta-oxidation of fatty acids a highly oxygen-demanding process when compared to glucose oxidation.
Essentially, by lowering carnitine levels, you reduce your body’s ability to burn fat for energy. Carnitine is needed to shuttle fatty acids across the mitochondria membrane into the mitochondria matrix where they can be burned for energy. This produces a shift of energy metabolism for your heart cells from fat burning to glucose burning (glycolysis), which requires less oxygen and is easier on your heart.
Meldonium has also been shown to act as an Organic Cation/Carnitine Transporter 2 inhibitor, which can decrease carnitine absorption. It should also be noted that meldonium can also decrease the production of trimethylamine N-oxide, which has been shown to be associated with atherosclerosis and congestive heart failure. 
Meldonium as a Performance Enhancer
In a Latvian study involving healthy, non-vegetarian human subjects, participants received either 500mg twice daily of meldonium or a placebo for 4 weeks showed an 18% decrease in plasma carnitine levels. Researchers also saw a two-fold increase in gamma butyrobetaine concentrations, as expected. 
Another study involving 55 patients with chronic heart failure after myocardial infarction showed significant improvements when treated with 500mg of meldonium, including reduction of glucose hypermetabolism (slowed down glucose breakdown) and a prolonged distance in a six minute walk test (and this was in non-healthy adults). 
So, how does this help with exercise performance? Well, as I stated earlier, meldonium inhibits carnitine synthesis, and carnitine is necessary to shuttle fatty acids into the mitochondria where they can be burned for energy. By lowering carnitine levels, your body cannot burn fat for energy efficiently so it will mainly use glycolysis or the burning of glucose for energy.
This is beneficial for performance for a few reasons. Firstly, burning fatty acids is not a very quick process and requires a lot of oxygen in order to oxidize these long chain fatty acids. Glucose is a much smaller molecule and requires less oxygen to metabolize it, and your heart performs at greater efficiency when it is using less oxygen.
You’ve probably been told by some “coach” during your life to carb-load before a workout or athletic event because normally your body will utilize carbs as its primary source of energy, as well as its first source of energy. Simple carbs, like glucose very readily enter your bloodstream and are burned for “quick” energy.
Fatty acids spend more time in your digestive tract and are slowly released into your bloodstream to be burned for energy. Specifically for aerobic exercise, glucose is the preferred macronutrient in your muscle cells. The longer you are training or exerting energy, however your body will switch over to burning fat for energy, typically around the 90-minute mark.
This is normally because your body has run out of accessible glucose. However, if you had an unlimited supply of glucose, you could theoretically train for a very, very long time.
Other possible ergogenic benefits from this drug are decreased lactic acid production (decreased soreness and fatigue), improved glycogen storage and utilization, improved heart function, and enhanced physical work capabilities. 5 All of this would translate very nicely to say, an elite endurance athlete.
Meldonium is an interesting compound that may increase performance in elite athletes via lowering carnitine levels in the body. WADA added it to its banned list in January of 2016, with conflicting statements on if it truly can exert ergogenic benefits.
In my opinion, there is some verifiable human research, as well as mammal data to show that it can aid in increasing performance by decreasing oxygen consumption and lactate production. Typically, the dosing protocol is 500-1000mg taking twice daily for 2-3 weeks during training period and 10-14 days prior to competition.
For those of you being drug tested, the half-life is somewhere between 6-14 hours, and can be detected 2-4 days after discontinuing.
Overall, this is a very unique class of performance enhancing compounds, and the biochemistry is very cool to me. Meldonium seems to have an excellent safety panel, especially compared to earlier drugs which inhibited the enzyme Carnitine PalmitoylTransferase-1 (CPT-1), in an attempt to elicit the same effect.
It just goes to show you that performance-enhancing compounds come from all types of prescription medications, and without having a coach/team scientist who understands biochemistry this drug probably never would have been used by so many athletes. See guys, science is pretty freaking cool.
2) Qi, Jiaqian; You, Tao; Li, Jing; Pan, Tingting; Xiang, Li; Han, Yue; Zhu, Li. "Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies". Journal of Cellular and Molecular Medicine: n/a–n/a. ISSN 1582-4934
3) Liepinsh, Edgars, et al. "Mildronate treatment alters ?-butyrobetaine and l-carnitine concentrations in healthy volunteers." Journal of Pharmacy and Pharmacology 63.9 (2011): 1195-1201.
4) Vasiuk I, Iushchuk EN, Shkol’nik EL, Khadzegova AB, Sadulaeva IA, Vit’ko NK, et al. Comparative trial of efficacy of trimethasidine MB and 3-(2,2,2-trimethylhydrasine) propionate dihydrate in chronic heart failure. Ter Arkh 2007;79:51–8
5) Lippi, Giuseppe, and Camilla Mattiuzzi. "Misuse of the metabolic modulator meldonium in sports." Journal of Sport and Health Science 6.1 (2017): 49-51.
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