Rachel Axon

USA TODAY Sports

Maria Sharapova is the most noteworthy athlete to have failed a drug test for meldonium, but in the month since the tennis star revealed her use of a drug that she contends is for medical reasons a slew of other top athletes have been implicated.

They include fellow Russians Yuliya Efimova, a four-time breaststroke world champion, and Nikolai Kuksenkov, the country’s best male gymnast. In all, 140 athletes have tested positive for meldonium in the three months after it was banned on Jan. 1, according to a World Anti-Doping Agency spokesman.

But as the tally of failed tests increases, critics are raising questions about its performance enhancing benefits and how WADA could ban the drug with what they say is relatively little scientific evidence.

“There’s really no evidence that there’s any performance enhancement from meldonium. Zero,” said Don Catlin, a long-time anti-doping expert and the scientific director of the Banned Substances Control Group.

Those supporting meldonium’s ban point to its potential to enhance performance and measures of its use by athletes, both before and since the ban.

Drug used by Maria Sharapova banned after tip to USADA

Those questions highlight a difficult position for WADA. With scant existing research, how does it know meldonium enhances performance? Does it need to ban a drug like meldonium before it understands its benefits and potential harms because it sees athletes using the drug? And if it’s not enhancing performance, why are a large number of seemingly healthy athletes taking a drug used to treat patients with heart problems?

Criteria for banning drugs

Meldonium’s journey to WADA’s prohibited substances list began in March 2014 when the U.S. Anti-Doping Agency received a confidential tip that Eastern European athletes were using the drug to enhance performance.

By October of that year, meldonium — which also goes by the brand name Mildronate — was on WADA’s monitoring list. In February 2015, scientists completed a study of global athlete usage of the drug.

In reviewing 8,320 urine samples, the study — which was funded by the Partnership for Clean Competition — found that 182 samples contained meldonium. At 2.2% of the sample, it was more than double the rate for any other drug on the list. While stating that the findings of meldonium in samples was not limited to a particular sport, the paper notes use of the drug was found to a greater extent in strength sports (67%) and endurance sports (25%).

Results from the European Games in Baku, Azerbaijan, in June seemed to support concealed use of the drug. That research, published in the British Journal of Sports Medicine, showed positive tests for meldonium in 66 of 762 urine samples but that only 23 athletes of the 662 athletes tested had declared their use of the drug.

Of the 662 doping-control forms the study reviewed, 525 declared the use of a medication or nutritional supplement. Use of meldonium was found in 15 of 21 sports, and the total count included 13 medalists.

While acknowledging evidence of meldonium’s performance enhancing effects is “limited,” the study concluded that since the drug was not being used primarily for therapeutic reasons it was “evidently being used with the intention to either improve recovery or enhance performance.”

To be considered for WADA’s prohibited list, a substance must meet two of three criteria: that it enhances or has the potential to enhance performance, that it presents an actual or potential health risk or that it violates the spirit of sport.

Once it was up for consideration, WADA’s expert group could consider public discussion on the drug, information from medical literature, monitoring, the availability of a test for the drug, among other factors.

In September, WADA decided to ban the drug and that went into effect on Jan. 1. In its explanatory note, WADA wrote that it was banned because of evidence of use with the intention of enhancing performance.

No clear answer on how long meldonium stays in system

Dr. Andrew Pipe, medical and scientific advisor to Canadian Centre for Ethics in Sport, acknowledged there is little English-language literature available on meldonium, which was created in Latvia in the 1970s and is not approved for use in the United States and many other Western countries.

But Pipe defended its addition to the list, saying that while he was not speaking for WADA that the committee did follow WADA’s process. In a statement, a WADA spokesman similarly noted that the agency followed its process in banning meldonium.

“If you have a substance that has a purported mechanism that is capable of enhancing performance, you have evidence it is being used by large numbers of athletes and you have evidence that it is used by a large number of athletes concealed, then I think you come to the conclusion that this is a substance that should be placed on the prohibited list,” said Pipe, who was chair of the expert group at the time.

Little scientific evidence

Catlin and others question whether meldonium meets the basic criteria to be considered for the list. It’s not that it doesn’t enhance performance, Catlin said, it’s that there’s not research to show that.

“They have to try to show that it enhances performance, but by banning it they’ve already said it enhances performance and that will make people turn to it,” Catlin said.

“You can find that it has effects, but it’s difficult to link those to performance enhancement,” said Catlin. “I’ve tried and tried to figure out why so many athletes seem to be taking it.”

The drug, which is used to primarily to treat heart and cardiovascular diseases, works by shifting cells’ metabolism from fatty acids to carbohydrates for energy, a process that requires less oxygen.

A 2002 paper from researchers at Tbilisi State Medical University in Georgia found the drug has a positive effect on the physical working capacity of judokas, concluding it did not have side effects. Research presented in 2012 at the Baltic Sport Science Conference found much the same, noting it was not on the doping list.

For its part, Grindeks, the company that manufactures Mildronate, says it is not a performance-enhancing drug because it prevents the death of ischemic cells and does not increase performance of normal cells.

In guidance issued after the drug was banned, the Finnish Anti-Doping Agency noted there is “little scientific evidence of meldonium being able to enhance athletic performance.”

WADA does not have to prove a substance’s performance enhancing effects, and athletes are not able to challenge a drug’s inclusion on the prohibited list.

Catlin contends WADA incorrectly used evidence of use as a criterion. While few question whether use of the drug violates the spirit of sport, the broadest of the three criteria, some question how much it meets the first two.

“If you take those criteria seriously, then you would think that substances need to be innocent before proven guilty,” said Roger Pielke Jr., a University of Colorado professor whose book, The Edge: The War against Cheating and Corruption in the Cutthroat World of Elite Sports, is due out this year. “You can just say here’s a substance, athletes are taking it therefore we have suspicion that it has performance enhancing effects. Your anti-doping list would expand very rapidly if any substance that out there and you just add it to the list.

“If evidence is to matter, then the meldonium ban was put into place before that evidence became readily available,” he added.

Getting that evidence is part of the problem WADA faces. First, there is the cost. Conducting a study of the drug’s effect on elite athletes that would include a big enough group to draw conclusions can be expensive.

Then there are ethical considerations. At what doses could a study give a drug, even to consenting participants? Athletes often ascribe to the theory that if some is good, more is better and might be doubling, tripling or even quadrupling the dosage, said Victor Conte, founder of BALCO.

Athletes would need an exemption to compete with the drug or be held out of competition for the duration of the study.

All of that can make it hard for WADA to respond to evidence of misuse of a drug by athletes.

“(It’s) extremely difficult given that WADA is not only underfunded, but it has to deal with several substances, many of which have effects that WADA is unable to determine due to lack of research and literature,” said Dr. Gregory Ioannidis, a sports lawyer and anti-doping expert in the United Kingdom.

While not impossible, conducting that research for each drug WADA considers banning presents a significant barrier. Without it, WADA faces the difficult position of banning a substance without knowing its effects.

“It does have the real potential to enhance performance,” said Dr. Tom Bassindale, anti-doping scientist and forensic toxicologist at Sheffield Hallam University in the United Kingdom. “It’s just there hasn’t been enough background research to prove that it does it yet.”

‘Rampant use’

So what can be concluded from the high number of athletes using meldonium?

Catlin found little reason behind Sharapova’s explanations, which included a magnesium deficiency and a family history of diabetes, and suggested there was little to infer from the number of failed tests other than that many athletes used meldonium.

But others accept the conclusion from some researchers and from WADA — that its use is at least with the intent to enhance performance.

“They must believe it does to all be on it,” said Bassindale. “It’s very hard to believe they all have angina or diabetes.”

For his part, Conte, who has worked to help anti-doping efforts after serving a prison sentence related to the BALCO case, said athletes’ use of meldonium is an endorsement of its performance enhancing effects.

“They know when it works. When you take drugs, you know when you’re stronger, faster, have more endurance,” he said.

“Of course it works. Now is there a double-blind, placebo-controlled, crossover clinical trial with a sufficient total of subjects involved to be published in a credible scientific journal? No. But is there rampant use of it in Olympic sports? Yes.”