Meldonium

Meldonium (also known as mildronate or mildronāts) is a drug that lowers the body's carnitine and so limits how much long chain fat the mitochondria can burn, shifting cells toward glucose oxidation. It was developed in the Latvian SSR in the 1970s and it is made by Grindeks, and it is used as a heart medicine in Eastern Europe and Central Asia, though it is not approved by the US Food and Drug Administration. It has been prohibited in sport since 1 January 2016. In "The Generality of Adaptogens," blocking carnitine-dependent fat oxidation is described as a way to protect cells under stress, because fatty acids released by the stress response can damage mitochondria and drive lipid peroxidation. In "Coconut Oil," mildronate is identified as the substance discussed in that article and is described as protecting cells against stress partly by opposing carnitine.

Meldonium
Drug name	Meldonium (mildronate, mildronāts )
Chemical formula	C6H14N2O2
Solubility	Water soluble
Discovery year	Early 1970s
Recommended dose	500 to 1000 mg per day
Upper limit	1000 mg per day
Food sources	None (made as a drug)
Legal status	Prescription only. not approved by the US FDA; prohibited in sport by WADA since 2016
Ray's verdict	Protects cells against stress partly by opposing the action of carnitine.

Function/Mechanism of action

Meldonium is a structural analogue of gamma butyrobetaine, the immediate precursor of carnitine. Its main known targets are gamma butyrobetaine hydroxylase, the enzyme that makes carnitine, and the carnitine transporter OCTN2, and by inhibiting both it lowers carnitine levels and shifts cells toward glucose metabolism. It also inhibits carnitine acetyltransferase, competing with carnitine at its binding site. The fat versus glucose trade involved is the same competition described in the Randle cycle.

In the stress model described in "The Generality of Adaptogens," impaired oxidative energy production first raises glucose consumption for glycolytic energy, then goes on to trigger adrenaline to mobilize liver glycogen, and finally cortisol once glycogen runs out. Adrenaline and ACTH also mobilize fat from storage, and stress-released fatty acids can add to lipid peroxidation and damage the mitochondria. Because carnitine is required for the oxidation of long-chain fatty acids, the proposed mechanism is that its betaine analogues, which interfere with carrying fatty acids into the mitochondria, protect against the damage that stress or catecholamines would otherwise cause through fatty acid oxidation. The example is isoproterenol, a bronchodilator that damages mitochondria; blocking carnitine-dependent fat oxidation is described as preventing that damage. Carnitine antagonists are grouped with vitamin E and coconut oil as adaptogens (not to be confused with herbal adaptogens) that protect respiration by reducing lipid peroxidation. The article also links rapid oxidation of unsaturated fats with catecholamine heart damage and the heart damage of corn oil toxicity, which saturated fats protect against.

In "Coconut Oil," shorter-chain fatty acids are described as being metabolized without the carnitine transport system. The article identifies mildronate as the drug discussed in the earlier Adaptogens article and describes it as protecting cells against stress partly by opposing carnitine. Comparative studies are reported to have found that added carnitine had the opposite effect, promoting the oxidation of unsaturated fats during stress and increasing oxidative damage to cells. Short-chain saturated fats, which need no carnitine to enter the mitochondria, are proposed to receive priority for oxidation and therefore inhibit the oxidation of unstable, peroxidizable unsaturated fatty acids.

In mice given mildronate daily for 20 days, carnitine fell in plasma and heart, insulin stimulated glucose uptake in the heart rose by 35 percent, and the heart's levels of glucose transporter 4, hexokinase II and insulin receptor protein increased. In healthy volunteers taking 500 mg twice daily for four weeks, average plasma carnitine fell by 18 percent and urinary excretion of carnitine and gamma butyrobetaine rose; eating meat partly offset the effect.

Medical uses/Effects

In Latvia the product is marketed as part of combination therapy for reduced working capacity, physical and psycho-emotional overload, and recovery after cerebrovascular accident, traumatic brain injury and encephalitis. The Polish leaflet describes it as adjunctive treatment for mild, long term heart failure, with a recommended dose of 500 to 1000 mg per day (maximum 1000 mg) for 4 to 6 weeks.

In a 2006 rat study, a 10 day course of 200 mg/kg per day reduced infarct size during induced heart ischemia (43 percent of the risk zone versus 57 percent in controls) with no difference in heart rate, mean arterial pressure or frequency of arrhythmias. The paper appears in the references of "Suitable Fats, Unsuitable Fats," where its description of mildronate as an antianginal drug approved in parts of Europe is quoted.

"The Generality of Adaptogens" lists the reported effects of an unnamed Soviet-era adaptogen of the betaine class used as an animal-feed additive, based on a literature search by P. Hockstaff. The reports included protection of the brain against hypoxia, faster healing of wounds and burns, activation of immune responses, restored contractility in hypoxic heart tissue, prevention of falls in ATP, protection against catecholamine-induced heart injury and fatty diets, faster growth in chickens, very low toxicity, and use in a range of cardiovascular diseases. The article predicted that a cheap substance like this would meet resistance from the drug industry and the FDA. The article does not name the substance, but "Coconut Oil" identifies it as meldonium by referring back to the earlier discussion. The animal-feed use fits Wired's report that meldonium's inventor, Ivars Kalviņš, first developed it in the early 1970s for use on livestock, with human use following about a decade later.

Military use

In the Soviet-Afghan War, soldiers were given meldonium to combat extreme altitude oxygen deprivation, combat and physical stress, allowing soldiers to continue under extreme conditions. The Associated Press reported that Kalviņš told Diena in 2009 that soldiers fighting in Afghanistan in the 1980s were given the drug, pointing to the high altitudes, the oxygen deprivation, and long runs with full gear after which soldiers could develop ischemia. He added that the soldiers were not aware they were being given it, and said it was not doping, but allowed the body to withstand more physical pressure while still spending its reserves.

Use in sport

Meldonium became prohibited under the World Anti Doping Agency's rules on 1 January 2016. By mid April 2016, 172 athletes had failed tests for it. WADA said that its decision followed a review between 2011 and 2015, including a 2015 monitoring program that revealed a high prevalence of use by athletes, and that claims of performance enhancement had been made by various authors, including the manufacturer. Grindeks itself said it believed the drug would not enhance performance in competition and might even do the opposite.

The most prominent case was tennis player Maria Sharapova, who tested positive for meldonium at the Australian Open in January 2016 and received a two year ban from the International Tennis Federation; the Court of Arbitration for Sport cut it to fifteen months on 4 October 2016, with the ban counted from 26 January 2016. She said she had first been prescribed the drug for medical reasons in 2006 and had not known it had been banned.

UFC lightweight Islam Makhachev was due to fight Drew Dober at UFC on Fox 19 on 16 April 2016, but after the weigh ins the UFC announced he had failed an out of competition drug screen for meldonium and the bout was cancelled. On 27 July 2016 USADA announced that his sample, taken on 4 April 2016, was positive but that he had ingested the substance without fault or negligence. It reported that he had a radiofrequency ablation for frequent ventricular arrhythmia in December 2014, that his physician recommended meldonium (a nonprescription medication) in November 2015 as part of follow up treatment, that he used it for four weeks from late November to late December 2015, and that he stopped before the ban took effect. USADA concluded that the extremely low concentration was consistent with use before the ban and, following WADA's guidance of 30 June 2016, gave him no period of ineligibility.

Makhachev later told UFC Russia, ahead of his lightweight title fight against Charles Oliveira, that Russian national team were given mildronate like vitamins, according to a Sportskeeda report of the interview.

Risks

The leaflet calls meldonium usually well tolerated. Common effects are allergic reactions, headache and gastrointestinal discomfort; increased heart rate and lowered blood pressure are very rare; eosinophilia, excitement and weakness occur with unknown frequency. It should not be taken during pregnancy or breastfeeding, is not for children, and calls for caution in chronic kidney or liver disease. It may strengthen the effect of nitroglycerin, nifedipine, beta adrenolytics, blood pressure lowering medicines and peripheral vasodilators, and an overdose may cause low blood pressure, headache, dizziness, rapid heart rate or weakness.

Because meldonium lowers carnitine and with it mitochondrial fatty acid oxidation, fat can build up in the liver. In a 2024 study, mice fed a high carbohydrate diet containing meldonium for 21 days developed hepatic steatosis, and reduced plasma carnitine and acylcarnitines confirmed that their fatty acid oxidation was impaired. The steatosis developed despite the high carbohydrate diet, and the authors found that increased fat synthesis did not explain it. The mice received about 550 mg of meldonium per kilogram of body weight per day, whereas the Polish leaflet's maximum dose for adults is 1000 mg per day.

The main open question is what sustained carnitine depletion does in healthy people. An editorial in the Postgraduate Medical Journal pointed to earlier studies of carnitine depletion caused by pivalic acid containing antibiotics, in which a moderate fall in muscle carnitine reduced work capacity at maximal oxygen uptake in healthy volunteers and, in a separate study, left ventricular mass, though it judged that meldonium at recommended doses would not have so drastic an effect. The protective interpretation of carnitine antagonists concerns stress and lipid peroxidation, not the safety of long-term use.

Alternatives

The cited articles name other ways to protect respiration and cut lipid peroxidation without a drug. The main alternative is coconut oil: its short- and medium-chain fatty acids are metabolized without the carnitine transport system, and the article describes dietary coconut oil as reducing the need for vitamin E and having direct and indirect antioxidant activity. The Adaptogens article also presents thyroid hormone as the basic anti-stress hormone because it is essential for respiratory energy production, and includes magnesium, which stabilizes ATP, and dietary eggs among the adaptogens. The fats article adds that sugar helps by lowering free fatty acids.

See also

• Adaptogens
• Carnitine
• Coconut oil
• Randle cycle
• Harm reduction