This is actually displayed on the same floor as my research lab.

Tennis Note #31

Meldonium Demystified: Getting to the Heart of the Science

Since Maria Sharapova tested positive for a newly banned drug called Mildronate (Meldonium), hundreds of other athletes have followed. There has been quite a conversation on how WADA [World Anti-Doping Agency] dealt with the situation and eyebrows raised towards these athletes who are taking a drug clinically prescribed for heart problems. Sharapova reasoned her doctor prescribed it for irregular EKG results, magnesium deficiency and a family history of diabetes. Here are all the questions I addressed, based on my own curiosity and train of thought:

  1. Who invented mildronate?
  2. Who is using mildronate? How much? How long does it last?
  3. Why ban it?
  4. Why is meldonium a treatment for ischemia? What does it do?
  5. How can mildronate potentially benefit diabetic patients?
  6. What role does magnesium play in the body?
  7. How can mildronate potentially benefit athletes?
  8. How can the inventor argue it is not performance enhancing, if his own “finding” is leaning that way?
  9. From a scientific perspective, is there reasonable doubt?
  10. What is a good next step?

Disclaimer: I am not a biochemist. I am a 4th year PhD student in bionanotechnology with a background in applied physics and mechanical engineering. However, I have taken and TA-ed the basic biology needed to understand the process and currently teach a course on biomechanics. In addition, the research lab I work in specializes in cardiovascular engineering and cell mechanics. Lastly, I had someone who has taken biochemistry verify my understanding.

Who invented mildronate?

Professor Ivars Kalvins, director of the Latvian Institute of Organic Chemistry, invented mildronate about 40 years ago. We have an official statement on record from the Prof. Kalvins against this ban of his drug from WADA, stating there is no scientific evidence that meldonium is a performance enhancing drug [he is not wrong] and it simply protects the heard for overexertion. If you search for papers on mildronate, many of them will have his name on them but I could not find an original paper from 40 years ago.

Who is using mildronate? How much? How long does it last?

Dr. Christian Schneider and colleagues published a study entitled, Meldonium use by athletes at the Baku 2015 European Games, in the British Journal of Sports Medicine, identifying athletes from Latvia, Russia, Ukraine, Georgia, Kazakhstan, Azerbaijan, Belarus, Uzbekistan, Moldova, and Kyrgyzstan. The main conclusion from the study:

The laboratory findings of 66 positive results for meldonium out of 762 (8.7%) samples and the active surveillance undertaken by the EOC Medical and Anti-Doping Commission, show the widespread use of this drug by athletes competing at the Baku 2015 European Games. These findings highlight the excessive and inappropriate use and prescribing of this prescription drug in a generally healthy athlete population.

Another interesting result:

A total of 23 of the 662 (3.5%) athletes tested between 8–28 June declared the personal use of meldonium at the time of the Games.

The typical doses for prescribed meldonium: 500 mg-1g daily.

The estimated concentration for these athletes in the study based on urine samples [athletes are required to provide 90 mL of urine]: 7 to 273 ug/mL and those 66 positive results correspond to 100 ng/mL or more [1,000,000 ng = 1 mg //1000 ng = 1 ug].

How much of the drug is your body over time? If I am interpreting this correctly, the first part is solely due to distribution of the drug within the body and the second part is the actual excretion from the body. To put this into context, caffeine has a half life of 5–6 hours.

The notice WADA issued to the stakeholders had some preliminary findings on the drug’s lifetime so I tried to illustrate it loosely. The half-life curve is important in order to estimate when an athlete ingested meldonium based on the concentration measurement at a particular time. However, they also state this type of data is very preliminary. Based on this model, and their ingestion time and amount prediction, they have described how they will proceed.

Why Ban It?

The last statement I want to quote from this particular paper is about the evidence of meldonium as a performance enhancing drug:

The evidence to demonstrate any performance enhancing effects of meldonium in the athlete population is limited. There appears to be some evidence that meldonium may benefit exercise performance in rodents, but specific studies to evaluate potential effect on performance specifically in elite athletes have not been identified.

The authors then proceed to highlight some research that I will address shortly, but first, a quick question. Why ban it if there is no evidence? Short answer: if it checks at least two boxes, then it goes on the prohibited list.

This information was found here.

Why is meldonium a treatment for ischemia? What does it do?

From one of Prof. Kalvin’s papers:

Biochemical and pharmacological evidence supports the hypothesis that the mechanism of action of mildronate is based on its regulatory effect on carnitine concentration, whereby mildronate treatment shifts the myocardial energy metabolism from fatty acid oxidation to the more favorable glucose oxidation under ischemic conditions.

Alright, let me attempt to simplify this jargon for you.

Image from here.

There is a supply and demand relationship for oxygen within the heart and we can characterize the heart’s efficiency as the amount of work produced [pumping action] by the heart per energy [oxygen] consumed. When you have ischemia, there is an imbalance in this relationship. Thus, the goal of mildronate is to optimize oxygen consumption without altering heart functionality. The way Prof. Kalvins’ group approaches this problem is with a drug that alters the normal way a cell metabolizes energy. Hold on, what does that mean?

Image taken from Khan Academy. Click it to be redirected and learn more! The goal is to produce energy or ATP, but also use the least amount of oxygen. This entire process of converting fuel to energy by way of oxygen is also known as cell respiration.

When you eat your breakfast, lunch, or dinner — you ingest a certain amount of proteins [amino acids], carbohydrates [sugars]and fats [fatty acids] . Depending on the category, our cells break down each ‘fuel source’ with a particular cycle and converts it into energy [ATP] at the cost of oxygen. Mildronate shifts the entire metabolism process from the fatty acid pathway to the glucose pathway. Why is this significant? The fatty acid pathway requires the most oxygen to produce energy among these different fuels. In addition, it is said that an increase in fatty acids inhibits the glucose pathway. Thus, mildronate is basically giving us more bang for our buck — produces more energy with the requirement of less oxygen.

How does this relate to ischemia? In ischemia, you have elevated rates of fatty acid oxidation and decreased rates of glucose oxidation. Mildronate would shift the metabolism pathway towards better cardiac efficiency. Where does carnitine come into the picture? The simple answer: Carnitine is a substance [found in dairy/meat] that just helps your body convert fat into energy. It regulates the amount oxidized and therefore, controls this balance we talked about earlier. Mildronate reduces the production of carnitine.

How can mildronate potentially benefit diabetic patients?

We just discussed this metabolism process earlier and one important part of this process is glucose [from carbohydrates]. There are two hormones called insulin and glucagon that help regulate levels of blood sugar (glucose) levels in your body. Insulin inhibits the fatty acid oxidation, glucagon increases it, and the balance between the two maintain the fatty acid oxidation equilibrium.

The delicate balance of insulin and glucagon. Taken from Khan Academy! Click the image to learn more!

When you have type 1 diabetes, your body does not produce insulin. When you have type 2 diabetes, your body produces insulin but does not respond well to it. If you have some inhibition of insulin, then this delicate balance tips towards increased fatty acid oxidation and recall, this would leave the cells oxygen deficient. Thus, a drug like mildronate could potentially benefit diabetic patients by restoring the original equilibrium. Has this been tested? Only in type 2 diabetic rats and it was found to improve blood glucose levels.

What role does magnesium play in the body?

Sodium [Na], potassium [K], calcium [Ca], and magnesium [Mg] play important roles in the body. A review paper states,

[D]ietary Mg deficiency plays an important role in the pathogenesis of ischemic heart disease, congestive heart failure, sudden cardiac death, cardiac arrhythmias, vascular complications of diabetes mellitus, pre-eclampsia/eclampsia and hypertension.

Magnesium is not only involved in the energy metabolism we discussed earlier but also in cell signaling. To explain this, I found a great analogy. Do you remember playing ‘telephone’ as a kid? One person has a message and must whisper it into their neighbor’s ear. The neighbor must then relay the message to the next person. It continues down a line until the last person must announce they final message and it is nothing related to the original statement because of some communication issue.

Taken from Khan Academy. Learn more about cell signaling by clicking the image!

Good communication is key for our cells to work together and if there is some sort of communication issue, it probably describes some disorder or disease. Everything depends on sending and receiving these messages clearly between cells in order to coordinate major events in the body like growth and development, or for our purposes, a heart beat. There are three major steps in cell communication: signal reception, signal transduction, and cellular response. Each cell has a bunch of different receptors on its membrane. Basically each receptor is like a door and a there is a particular key to unlock each door. Once unlocked, a cascade begins [signal transduction] like passing a baton in a relay race until it reaches a destination where a decision is made [cellular response] on how to respond. Magnesium is part of this relay race. For the heart, it is well known (and measured) that the signaling begins at one end of the heart and propagates to the other end and the full response is a heart beat. Magnesium, like the other players I mentioned at the beginning, are charged particles, so this signal can actually be measured electrically via an electrocardiogram [EKG]. Just as a reminder, Sharapova mentioned something about an irregular EKG result and magnesium deficiency. If you want to learn more, I actually just taught a lecture on this subject.

How can mildronate potentially benefit athletes?

It turns out a student of Prof. Kalvins gave a presentation entitled, Mildronate increases aerobic capabilities of athletes through carnitine-lowering effect, at a 2012 sports science conference. According to this,

Mildronate is usually administered to athletes perorally in dose 0.5–1.0 g twice a day before training, as 14–21 day course during training period and 10–14 days before competitions

We talked earlier about mildronate generating energy with less amount of oxygen. For athletes, in addition to the heart, the other muscles also work the same way. High intensity training causes a reduction of blood flow to the muscles, and with that, a depletion of oxygen [oxygen transport via red blood cells]. In order to produce energy, the muscle cells must undergo a process called glycolysis, illustrated in the original metabolism diagram. The process of glycolysis can quickly generate energy, in comparison to the full process of oxidation, but with the price of lactic acid buildup. Lactic acid is responsible for your body feeling sore and tired. If these athletes take mildronate, then these muscle cells undergoing high physical loads do not require as much oxygen per energy molecule, and you can extend your training time.

How can the inventor argue it is not performance enhancing, if his own finding is leaning that way?

Here is the thing. This was written in an abstract for a conference, which means it was either a poster or a presentation. The aim of the study was simply to review previous literature data, not actually conduct a study. They claim that there are 25 articles directly related to the effects of mildronate on physical work capabilities but only cite one from 2002 — Effect of Mildronate on physical working capacity of highly qualified judokas. I have tried to track down this paper but I still cannot find it. Other recent papers continue to cite it but a little insider information about work cited in research papers: many times authors will see how a citation is used in another article and just copy and paste the citation without reading the article. Especially if you write only one sentence about mildronate in the context of sports performance. It should be noted, the one paper that keeps popping up, which I just linked, is not about mildronate’s effect on sports performance. It is about testing urine samples in a particular manner, as are a few other papers, and as far as I can tell from the last author, it is basically a ‘WADA paper’.

From a scientific perspective, is there reasonable doubt?

The mechanism by which mildronate works could theoretically improve athlete endurance because it protects the muscle cells in an oxygen depleted state. Also, the inventor claims there is no major health risk towards the athletes. However, there is no direct scientific evidence which illustrates a statistically significant improvement in humans. Every piece of evidence I have seen is circumstantial at best — which is all WADA really needs.

Do not ask me what the last one means. I did not bother looking it up.

Why is actual scientific evidence important? Because we do not know how much athletes would need to take in order for it to have significant effect on performance. Now, there is one study that got my attention entitled Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial, and at first glance, the conclusion states:

This study has revealed the superiority of the treatment with Mildronate (1 g/day) in combination with a standard therapy for the exercise tolerance of patients with stable angina pectoris over the treatment with placebo in combination with a standard therapy.

However, there is something I need to point out about the study design. “The study was a prospective, randomized, double-blind, placebo controlled phase III trial with two treatment groups.” From a pool of patients with chronic coronary heart disease, they basically gave the drug or gave a placebo and then tested each person’s ability to perform an exercise tolerance test. This is great if you want to look at the specific effects of a drug on a patient group [which was their intent] but this cannot be cited as proof for performance enhancement in the context of sports. Why? Because they did not test normal healthy human subjects. As someone who works directly with human blood, you always need a baseline and you need to conduct that test multiple times with different subjects because there is always person to person variability.

Dr. Joyner, quoted in a Forbes article, stated:

I would be shocked if this stuff (meldonium) had an effect greater than, say, caffeine or creatinine (a natural substance that, when taken as a supplement, is thought to enhance muscle mass), if any effect at all.

Well, it is a fair statement because we do not know. We barely even understand how long the drug stays in an athlete’s body. Is there reasonable doubt? Yes. Until there is hard evidence, it will always be inconclusive. Is it fishy that so many athletes from these regions are taking this drug? Honestly, no. The drug is readily available in these regions and marketed to help athletes [with little evidence]. It may not be FDA approved but newsflash, the United States is not the center of the universe when it comes to pharmaceuticals, and I am sure there are similar drugs on market here that do not want the competition from a possible superior drug. Even if it tried to get FDA approval, it most likely would need to go through any and all clinical trials once again. Why bother when you have a market and approval elsewhere? If anything, with such little evidence, you have to wonder how much money was made selling mildronate under the possible false pretense of superior performance.

What is a good next step?

For WADA, I would say learn more about meldonium before drawing conclusions. Just because a number of athletes take a particular drug, does not mean the drug itself causes significant performance enhance effects. Drawing conclusions based on the appearance of a trend is not science. We have seen this before in tennis. Novak Djokovic stopped eating gluten and suddenly became a dominant no. 1 player. Andy Murray and many others tried to do the same and it had adverse effects. Why? Because the latter players drew a conclusion based on the appearance of a trend when in reality, the former’s performance improved because he had an allergy to gluten. Yes, there appears to be a correlation, but WADA needs to determine the true effects of different meldonium dosage. If they are correct after all, then case closed. Until then, I will continue to watch this unfold with scrutiny.

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