meldonium

meldonium, drug used to protect against tissue damage caused by ischemia—a reduction in blood flow to a part of the body, resulting in decreased oxygen availability in affected tissues. Meldonium is typically used as a cardioprotective agent to defend against ischemic damage to the heart and in the treatment of certain neurological conditions involving ischemia. Meldonium is marketed under the trade names Mildronate and Mildronāts and is manufactured and sold by the Latvian pharmaceutical company Grindeks.

Discovery and uses

Meldonium was designed in the 1970s by Ivars Kalvins, a scientist at the Latvian Institute of Organic Synthesis. At the time, the drug was under investigation for its ability to promote growth in animals. The following decade, it was given to Soviet soldiers who were fighting in Afghanistan to help increase their stamina at high altitude. Meldonium was later registered for use in the treatment of coronary heart disease, angina pectoris (chest pain), and cerebrovascular disease in Russia as well as in various other republics that were then part of the Soviet Union, including Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Ukraine, and Uzbekistan.

Mechanism of action

Meldonium exerts its effects by blocking the actions of an enzyme known as gamma-butyrobetaine dioxygenase (GBB). GBB is involved in the production of carnitine, a vitamin-like substance that is closely related to the amino acids and that serves an important role in the transport of long-chain fatty acids for energy metabolism. However, fatty acid transport and oxidation is highly demanding in terms of oxygen consumption, and, in the presence of oxygen deficiency, toxic intermediate compounds formed during fatty acid metabolism accumulate within cells.

By blocking GBB and carnitine synthesis, meldonium causes a decrease in fatty acid metabolism. That forces cells to generate energy through such pathways as aerobic glucose metabolism and glycolysis, which require significantly less oxygen to generate energy in the form of adenosine triphosphate (ATP). Thus, overall, compared with fatty acid oxidation, glucose metabolism and glycolysis generate more ATP per molecule of oxygen. In leveraging highly oxygen-efficient metabolic pathways, meldonium is thought to help restore the balance between demand and supply of oxygen within cells that are affected by low-oxygen conditions, such as those associated with ischemia or exposure to high altitude.

Use in athletes

Meldonium is a suspected performance-enhancing drug, with potential for abuse by athletes. In January 2016 it was added to the World Anti-Doping Agency list of banned substances, owing to its widespread use in athletes from Russia and eastern European countries, where the drug is readily available. The drug gained particular notoriety in March 2016 after Russian tennis player Maria Sharapova announced that she had tested positive for it earlier in the year at the Australian Open. That same year, players on the Russian national under-18 hockey team tested positive for meldonium prior to the ice hockey U18 World Championships. For the competition, the entire team was replaced with players from the country’s under-17 roster.

Meldonium is suspected of enhancing athletic performance through its ability to protect cells against detrimental effects of ischemia and potentially facilitate improved rehabilitation following exercise. However, whether the drug actually increases endurance or otherwise benefits athletic performance is uncertain.

Side effects

Meldonium appears to have few side effects. Those that have been reported include decreased blood pressure, dizziness, headache, increased heart rate, nervousness, and sleeplessness. Research in animals suggests that long-term treatment with meldonium potentially increases behaviors linked to anxiety and causes an imbalance in the types of microorganisms that constitute the gut microbiome.