What is the mechanism of action of meldonium (mildronate) as a performance-enhancing drug (PED)?

Meldonium as a Performance-Enhancing Drug: Mechanism of Action

Meldonium functions as a performance-enhancing drug primarily by inhibiting carnitine biosynthesis, which redirects cellular metabolism from fatty acid oxidation to glucose oxidation, thereby reducing lactate accumulation, enhancing glycogen utilization, and protecting against exercise-induced oxidative stress. 1, 2

Primary Mechanism: Metabolic Modulation

Carnitine Pathway Inhibition

• Meldonium acts as a competitive inhibitor of γ-butyrobetaine hydroxylase (BBOX), the enzyme responsible for the final step in carnitine biosynthesis 2
• This inhibition decreases endogenous carnitine levels throughout the body, fundamentally altering cellular energy metabolism 3
• The drug also blocks intestinal absorption of dietary carnitine via the organic cation/carnitine transporter 2 (OCTN2) 2

Metabolic Shift from Fat to Glucose Oxidation

• By reducing carnitine availability, meldonium impairs mitochondrial β-oxidation of fatty acids, since carnitine is essential for transporting long-chain fatty acids into mitochondria 1, 3
• This forces cells to redirect fatty acid oxidation to peroxisomes while simultaneously activating glycolysis as the primary energy source 2, 3
• The metabolic shift mimics a "pharmacological training effect" on myocardium and skeletal muscle, even without physical activity 3

Performance-Enhancing Effects

Enhanced Aerobic Capacity and Endurance

• The preferential use of glucose oxidation over fatty acid oxidation is more oxygen-efficient, producing more ATP per molecule of oxygen consumed 1
• This results in decreased lactate production during and after exercise, delaying the onset of anaerobic metabolism 2
• Athletes experience improved aerobic endurance and enhanced exercise capacity through this mechanism 1, 4

Improved Recovery and Training Capacity

• Meldonium reduces the accumulation of toxic lipid peroxidation products and acyl/acetyl-carnitines that cause oxidative stress and mitochondrial dysfunction 2
• The protective effect against oxidative stress shortens recovery times between training sessions, allowing higher intensity and frequency of training 2, 4
• Enhanced glycogen storage and utilization further support sustained performance 2

Cardiovascular and CNS Benefits

• The drug demonstrates cardioprotective properties by reducing ischemic damage and improving cardiac function 1, 3
• Meldonium enhances central nervous system function activation, potentially improving focus and mental performance during competition 4
• It stimulates endothelial nitric oxide synthetase (eNOS) via PI3K and Akt kinase pathways, improving microcirculation and tissue perfusion 5

Clinical Context and Anti-Doping Status

WADA Classification

• The World Anti-Doping Agency added meldonium to the S4 list of prohibited metabolic modulators in January 2016 after monitoring its prevalence among elite athletes throughout 2015 1, 2
• Surveillance data revealed alarming widespread use among professional athletes prior to its prohibition 1, 4

Important Caveats

• Despite widespread athletic use, the evidence for performance enhancement remains largely observational and mechanistic rather than derived from rigorous controlled trials in athletic populations 1
• The drug is registered and available primarily in Baltic countries and former Soviet republics, with no marketing authorization in the European Union 2
• No serious adverse effects have been reported by manufacturers, though comprehensive safety data in athletic populations are limited 1

The mechanism underlying meldonium's performance-enhancing effects centers on its ability to optimize cellular energy metabolism under conditions of high oxygen demand, making it particularly attractive for endurance athletes and those requiring rapid recovery between intense training sessions.