Tennis star Maria Sharapova has admitted to using the performance-enhancing drug meldonium, which boosts brain and body power and endurance. Here’s how it works.
Meldonium was developed for the Soviet military and given to Soviet soldiers in the Afghanistan invasion. The drug increases endurance for physically and cognitively demanding tasks when the body is under physiological stress. Also known as mildronate, the drug has since been used for various medical purposes, notably for treating cardiac conditions and diabetes, but also for many neurological disorders including stroke, Parkinson’s, Alzheimer’s disease, and others. The drug is not available for use in the United States.
Meldonium works like an octane booster in gasoline to increase the power produced by the body’s metabolic machinery inside the mitochondria of cells. Mitochondria produce cellular energy by a metabolizing the sugar, glucose, in a reaction that requires many steps and produces a sequence of intermediate products and byproducts to ultimately synthesize the high-energy phosphate bonds in ATP–the fundamental fuel for all cells in the body.
One of the important molecules in cellular metabolism is L-carnitine, which is required for transporting molecules, called fatty acids, into the mitochondria of cells. Meldonium lowers the amount of L-carnitine in cells. The cells respond to this by increasing other molecules on the membrane of mitochondria that suck L-carnitine into the organelles (carnitine palmitoyltransferase-1) and also by several other metabolic changes to compensate for the lower levels of L-carnitine. Another effect of melodium is to stimulate insulin-dependent glucose uptake into cells, which makes the drug useful as an anti-diabetic medication.
The result of these compensatory cellular responses is that, melodium protects mitochondria from being damaged under conditions of cellular stress, notably when oxygen, glucose, or blood flow are reduced. Extreme physical activity (for example marching with heavy packs in an army, climbing mountains, or competing at world-class level in tennis) depletes the blood of glucose and oxygen, and the performance of muscles, neurons, and other cells suffers, like a sputtering racecar running out of gas. Chronic physiological stress can lead to wide-spread cellular injury or death of many types of cells.
Such a fundamental effect on cellular metabolism from meldonium will have a wide range of effects including many effects on the brain. In studies on laboratory animals, meldonium has been shown to protect neurons from death caused by lack of oxygen, reduced blood flow, and certain neurotoxic substances. For example in a rat model of Parkinson’s disease, melodium protected neurons from death (Klusa et al., 2013). Cognitive enhancement by melodium has been shown in studies of learning and memory in rodents (Klusa et al., 2013; Beitnere et al., 2014), and the compound has been suggested as potentially useful to enhance cognition in patients with neurodegenerative diseases that result in dementia.
Sharapova denies taking the drug to cheat in competitive tennis. Meldonium was only banned as a performance-enhancing drug in January, 2016, but Sharapova states that she has taken the drug for a decade because of a family history of diabetes.
Beitnere, U., et al., (2014) Carnitine congener mildronate protects against stress- and haloperidol-induced impairment in memory and brain protein expression in rats. Eur. J. Pharmacol. 745: 76-83.
Birnbaum, M. Drug linked to Sharapova rooted in Soviet military, The Washington Post, March 9 2016
Dambrova, M., et al., (2016) Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity. Pharmacological Research, on-line in advance of print. Doi 10.1016/j.phrs.2016.01.019.
Klusa, V. (2013) Mildronate enhances learning/memory and changes hippocampal protein expression in trained rats. Pharmacol. Biochem. Behav. 106: 68-76.
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