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Cited by 26Doping in SportsPharmacological Effects and AssaysSports Performance and Training

The Inclusion in WADA Prohibited List Is Not Always Supported by Scientific Evidence: A Narrative Review

Open access
Bezuglov, Eduard, Talibov, Oleg, Butovskiy, Mikhail, Khaitin, Vladimir, Achkasov, Evgeny, Waśkiewicz, Zbigniew, Lazarev, Artemii·2021·Asian Journal of Sports Medicine
DOI 10.5812/asjsm.110753
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Abstract

Context: Our goal was to review the current literature regarding the ability of substances that have recently been included in the WADA prohibited list (i.e., meldonium, trimetazidine, xenon, and cobalt) or in the monitoring program (i.e., ecdysterone and bemethyl) to enhance performance in athletes or cause adverse effects. Evidence Acquisition: To find out which studies led to the prohibition of the substances mentioned, we searched the PubMed database using keywords including the substances’ or methods’ names, as well as phrases related to various aspects of sports activities and health assessments of athletes. Results: The results obtained during our systematic literature search clearly indicate that there is a lack of scientific evidence supporting the impact of several substances prohibited by WADA (i.e., meldonium, trimetazidine, xenon, and cobalt) on athletic performance or on health in athletes. Conclusions: There is insufficient evidence that the previously mentioned substances have any performance enhancing potential. If left on the list, meldonium may be classified as a “specified substance” because of its wide availability and due to the fact that this drug that can be easily bought over the counter without a prescription.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review searched PubMed in December 2019 and argues that WADA’s bans of meldonium, trimetazidine, xenon, and cobalt lack high-quality scientific evidence for performance enhancement or athlete health effects. It contrasts these with ecdysterone, whose WADA-funded study was judged most compliant with modern standards, and calls for publication of the evidence used in prohibited-list decisions.

Key findings

For meldonium, trimetazidine, xenon, and cobalt, the review found no high-quality published evidence supporting performance enhancement or adverse effects in athletes; Table 1 reports no meta-analyses or systematic reviews and only 2 RCTs total (xenon and ecdysterone). Meldonium: 498 athletes were disqualified after its prohibition, 25% of all punished athletes in 2017 were suspended for meldonium, and 8.7% of doping tests at the Baku 2015 European Games were positive for meldonium. Trimetazidine: detected in 0.23% of samples in the Warsaw lab (2008–2013) and 0.1% in Cologne (1999–2013); only two sports-medicine works were found, including one RCT in non-athletic volunteers published in 2017, three years after the 2014 ban. Xenon and cobalt: xenon was banned in 2014, but relevant studies were published after prohibition and found no performance enhancement; cobalt was banned in 2018, and a 2019 meta-analysis found no high-quality evidence that it affects athletic performance. Ecdysterone: WADA’s approach was the most compliant with scientific standards; in the 2019 WADA-funded study, supplements labeled as 100 mg ecdysterone actually contained 6 mg, and the study reported positive effects on anthropometric and performance parameters.

Methods

Narrative review; PubMed was searched in December 2019 using substance/method names plus keywords including “athletes,” “performance,” “sport,” “doping,” “trained,” and phrases “adverse event” and “safety”; all queried studies were independently reviewed by two sports medicine physicians. Table 1 summarizes search hits and articles: meldonium 240 hits/127 English/6 keyword articles; trimetazidine 1053/836/2; xenon 11815/10116/3; cobalt 54992/46060/3; bemethyl 94/14/4; ecdysterone 2554/2389/4. Analysis is descriptive/narrative rather than a quantitative synthesis.

Limitations

Stated: the authors could not find high-quality evidence for several banned substances; they note WADA might have data not accessible to the public; many relevant studies were published in Russian, in non-indexed journals, or after the bans; and there were no meta-analyses/systematic reviews and few studies in athletes. Evident from the text: the search was limited to PubMed and to December 2019, with no formal systematic review protocol, no risk-of-bias or evidence-grading assessment, and reliance on absence of evidence. The review also notes language availability issues, e.g., only 127 of 240 meldonium articles and 14 of 94 bemethyl articles were in English.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.5812/asjsm.110753

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 47 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The vast majority of studies aimed at investigating the clinical efficacy of meldonium have been performed with sick persons.

    “The vast majority of studies aimed at investigating the clinical efficacy of meldonium have been performed with sick persons.”
    Quote in the paperSubstantial claim
  • Findingown data

    Only 2 RCTs in the PubMed database studied the ecdysterone and xenon influence on various performance aspects.

    “We could only find 2 RCT's in the PubMed-database that studied the ecdysterone and xenon influence on various performance aspects.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    WADA has shown no scientific evidence that meldonium has any effect on athletic performance.

    “However, the agency has shown no scientific evidence that this substance has any effect on athletic performance (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 2016, WADA Statement regarding Maria Sharapova case.

      Not checked in the free run.

  • Findingown data

    No published studies dated before 2017 were able to confirm the WADA President's statement that xenon can stimulate EPO and testosterone and therefore has potential to enhance athletic performance.

    “We could not find any published studies, dated before 2017 that were able to confirm this statement.”
    Quote in the paperSubstantial claim
  • Findingown data

    No study has investigated the effects of various trimetazidine concentrations on health or exercise performance in athletes or healthy volunteers.

    “We could not find any study that investigated the effects of various trimetazidine concentrations on health or exercise performance in athletes or healthy volunteers.”
    Quote in the paperSubstantial claim
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    Studies done with professional athlete participants are sporadic, and meta-analyses or systematic reviews are absent.

    “As we can see, the studies done with professional athlete participants are sporadic; meta-analyses or systematic reviews are absent.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The PubMed search yielded 240 articles regarding meldonium use in patients, including 12 reviews and 33 clinical trials.

    “Our PubMed Search request yielded 240 articles regarding meldonium use in patients, including 12 reviews and 33 clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Both studies on meldonium's possible performance enhancement were published after the prohibition of meldonium by WADA and contain references from several low-quality studies.

    “Both studies were published after the prohibition of meldonium by WADA and contain references from several low-quality studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Only 127 (53%) of articles from the meldonium literature search were available in English.

    “It must be noted that only 127 (53%) of articles from our literature search were available in English.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Only two works published in English regarding the possible ability of meldonium to enhance athletic performance exist, one of which is a narrative review.

    “We can note only two works published in English re- garding the possible ability of meldonium to enhance athletic performance, one of which is a narrative review (28,29).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] source

      Not checked in the free run.

    • cites [29] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    No data regarding positive bemethyl tests were found, probably because methods to detect it in biological fluids were developed only recently.

    “We could not find any data regarding positive bemethyl tests, probably because methods to detect it in biological fluids were developed only recently (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    A PubMed search for '20-Hydroxyecdysone' yielded 2554 hits, of which 2389 publications were in English.

    “We performed a PubMed search for “20-Hydroxyecdysone” that yielded 2554 hits, of which 2389 publications were in English.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Al-Kuraishy et al. showed that trimetazidine enhances psychomotor parameters in non-athletic volunteers; this work was published in 2017, three years after the WADA trimetazidine ban.

    “In the RCT conducted by Al-Kuraishy et al., the authors showed that trimetazidine enhances psychomotor parameters in non-athletic volunteers.This work was published in 2017, three years after the WADA trimetazidine ban (51).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is currently no high-quality published scientific evidence supporting the notion that trimetazidine enhances athletic performance or has any adverse health effects on athletes.

    “Thus, it can be concluded that there currently is no high-quality published scientific evidence supporting the notion that trimetazidine enhances athletic performance or has any adverse health effects on athletes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from studies in non-athletic volunteers or patients cannot be extrapolated to elite athletes.
    • Rests on an assumption: The absence of published high-quality studies showing performance enhancement or health effects in athletes means there is insufficient scientific evidence to support inclusion on the prohibited list.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Evidence based on low-quality studies often lacks control of confounding factors.

    “Moreover, evidence based on low-quality studies often lacks control of confounding factors (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is no high-quality published scientific evidence that supports the notion that meldonium enhances athletic performance or has any adverse effects on health in athletes.

    “Thus, based upon open-source data, it can be concluded that there is no high-quality published scientific evidence that supports the notion that meldonium enhances athletic performance or has any adverse effects on health in athletes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from studies in non-athletic volunteers or patients cannot be extrapolated to elite athletes.
    • Rests on an assumption: The absence of published high-quality studies showing performance enhancement or health effects in athletes means there is insufficient scientific evidence to support inclusion on the prohibited list.

  • Classified as probably not a substantial claim.

    Premisecitation

    The typical hierarchy of evidence value implies that randomized clinical trials and high-quality meta-analyses have the highest evidence value.

    “The typical hierarchy of evidence value implies that randomized clinical trials (RCT's) and high-quality meta-analyses have the highest evidence value (11)(12)(13).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (11)(12)(13)

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Stoppe et al. concluded that xenon increases erythropoietin levels in healthy volunteers.

    “In another study from 2016, Stoppe et al. concluded that xenon indeed increases erythropoietin levels in healthy volunteers (58).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vitale et al. demonstrated that trimetazidine improves exercise performance in patients with peripheral arterial disease, but they did not examine healthy volunteers or athletes.

    “Vitale et al. demonstrated that trimetazidine improves exercise performance in patients with pe-ripheral arterial disease, but they did not examine healthy volunteers or athletes (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dias et al. found that xenon inhalations lead to a slight, but long-lasting increase in endogenous erythropoietin production in non-athletic volunteers, but concluded that xenon inhalations did not enhance fitness or performance.

    “In 2019, 5 years after xenon inhalations were prohibited; Dias et al. tested the acute and chronic effects of various xenon concentrations on non-athletic volunteers and found that xenon inhalations lead to a slight, but long-lasting increase in endogenous erythropoietin production.Nonetheless, the authors concluded that xenon inhalations did not enhance fitness or performance (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is only minimal evidence from North America and Western Europe regarding the role of meldonium in the treatment of disease or whether it can produce meaningful performance enhancement in highly trained athletes.

    “There is only minimal evidence from North America and Western Europe regarding the role of meldonium in the treatment of disease or whether it can produce meaningful performance enhancement in highly trained athletes (19).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 2019, [State register of medicines].

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lippi et al. made assumptions that cobalt might be used for boosting erythropoiesis to gain performance advantages and expressed concern regarding possible adverse effects.

    “They have only made assumptions that cobalt might be used for boosting erythropoiesis to gain performance advantages, and they expressed concern regarding possible adverse effects (63,64).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] source

      Not checked in the free run.

    • cites [64] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The manufacturer's instructions state that meldonium is quickly metabolized and eliminated as two metabolites while Rabin et al. demonstrated a long second phase of elimination and urine excretion of parental entity in healthy volunteers.

    “The manufacturer's instructions state that meldonium is quickly metabolized and eliminated as two metabolites while Rabin et al. demonstrated that there was a long second phase of elimination and urine excretion of parental entity in healthy volunteers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Widespread use of meldonium among athletes from a particular region of the world is considered to be the reason for its prohibition.

    “Widespread use of meldonium among athletes from a particular region of the world is considered to be the reason for its prohibition.”
    Quote in the paperSubstantial claim
19 of 19

  • The paper relies on this without support.

    Findings from studies in non-athletic volunteers or patients cannot be extrapolated to elite athletes.

    “The vast majority of studies aimed at investigating the clinical efficacy of meldonium have been performed with sick persons.”
    “In the RCT conducted by Al-Kuraishy et al., the authors showed that trimetazidine enhances psychomotor parameters in non-athletic volunteers.”
    “Vitale et al. demonstrated that trimetazidine improves exercise performance in patients with pe-ripheral arterial disease, but they did not examine healthy volunteers or athletes (52).”

  • The paper relies on this without support.

    Animal studies cannot establish performance enhancement in athletes.

    “We could not identify high-quality scientific studies regarding the possible positive effects of bemethyl on athletic performance, but performance enhancement has been demonstrated in animal studies (68,69).”

  • The paper relies on this without support.

    The absence of published high-quality studies showing performance enhancement or health effects in athletes means there is insufficient scientific evidence to support inclusion on the prohibited list.

    “Thus, based upon open-source data, it can be concluded that there is no high-quality published scientific evidence that supports the notion that meldonium enhances athletic performance or has any adverse effects on health in athletes.”
    “Thus, it can be concluded that there currently is no high-quality published scientific evidence supporting the notion that trimetazidine enhances athletic performance or has any adverse health effects on athletes.”

  • The paper relies on this without support.

    WADA's inclusion decisions should be based on high-quality peer-reviewed scientific evidence.

    “Ideally, the decision to ban a substance should be made based upon the results of high-quality research published in peer-reviewed and indexed journals and according to WADA's own research and expert consultations.”

  • The paper relies on this without support.

    The systematic literature search captured all relevant scientific evidence on the substances, so absence of evidence in the search indicates a lack of scientific evidence.

    “The results obtained during our systematic literature search clearly indicate that there is a lack of scientific evidence supporting the impact of several substances prohibited by WADA (i.e., meldonium, trimetazidine, xenon, and cobalt) on athletic performance or on health in athletes.”
    “There is insufficient evidence that the previously mentioned substances have any performance enhancing potential.”

  • The paper relies on this without support.

    In the USSR, applications of ecdysterone were studied in various sports, but the results were published only in Russian non-indexed journals.

    “In the USSR, applications of this substance were studied in various sports, but the results were published only in Russian non-indexed journals.”

  • The paper relies on this without support.

    The quality of the USSR experiments on ecdysterone did not comply with scientific standards (no reference groups, open nonrandomized study design).

    “Moreover, the quality of these experiments did not comply with scientific standards (no reference groups, open nonrandomized study design).”

  • The paper relies on this without support.

    Expert opinion can be subjective or biased and therefore has low evidence value.

    “According to the principles of modern evidencebased medicine, expert opinion can be subjective or biased and therefore has low evidence value.”

  • The paper relies on this without support.

    Animal studies cannot establish performance-enhancing effects in humans.

    “In a different study by Isenman et al. (73), they provided a detailed review of ecdysterone, but the majority of tests they performed were done on animals.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The quality of most human studies on ecdysterone is often poor, raising the question of the validity of the results.

    “The quality of these studies is often poor, raising the question of the validity of the results.[Citation69]”

    From Ergogenic properties, safety evaluation and regulations of selected ingredients in testosterone booster dietary supplements (2024) · cites this paper as [69]

    The 20-Hydroxyecdysone (Ecdysterone) section says earlier Soviet sports studies lacked reference groups and used open, nonrandomized designs, calling their quality below scientific standards. That supports concern about those results, but the review does not say that most human ecdysterone studies are poor; it describes the later WADA study as compliant with modern scientific standards. No page number is available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Trimetazidine search-hit totals disagree

    Minor

    The text reports 1,055 PubMed results for trimetazidine, while Table 1 reports 1053 search hits for the same substance.

  • Claim that reviews are absent conflicts with a cited meta-analysis

    Minor

    The paper says meta-analyses or systematic reviews are absent, but later describes a 2019 meta-analysis concerning cobalt and athletic performance.

  • Count of four substances in section S2 conflicts with section assignments

    Minor

    The review covers four prohibited substances and two monitored substances, yet says four of the six are listed in S2. It separately places both meldonium and trimetazidine in S4, leaving at most two of the prohibited substances for S2.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 26

  1. 2018, 2018 anti-doping testing figures.
  2. 2015, World anti-doping code.
  3. 2019, The prohibited list.
  4. 2019, The 2019 monitoring program.
  5. 2020, The 2020 monitoring program.
  6. 2021, Prohibited list Q & A.
  7. 2021, Prohibited list expert advisory group.
  8. 2019, Funded research projects.
  9. Haynes RB, 1997, CMAJ., 157, 788
  10. Hiller SA, 1980, Le (triméthyl-2,2,2-hydrazinium)-3 propionate, procédé de préparation et application.
  11. Eremeev A, 1984, 3-(2, 2, 2-Trimethylhydrazinium) propionate and method for the preparation and use thereof.
  12. 2019, [State register of medicines].
  13. 2018, [List of vital and essential medicines for medical use for 2018].
  14. 2016, Annual report building an agency that is fit for the future
  15. Mundel T, 2012, Nicotine, exercise and heat stress: Performance benefits, health risks and implications for the prohibited list.
  16. Chiamulera C, 2015, Effects of snus administration on sport perfornance.
  17. 2016, WADA Statement regarding Maria Sharapova case.
  18. Kakhabrishvili Z, 2002, Ann Biomed Res Edu., 2
  19. Dzintare M, 2012, Curr Issues New Ideas Sport Sci., 5, 59
  20. 2014, The 2014 prohibited list international standard (version 2).
  21. 2014, Xenon added to banned substances list.
  22. [Ethylthiobenzimidazole hydrobromide].
  23. Dubovik BV, 1987, Farmakol Toksikol., 50, 116
  24. Syrov VN, 2008, Eksp Klin Farmakol., 71, 40
  25. Syrov VN, 1976, Farmakol Toksikol., 39, 690
  26. Chermnykh NS, 1988, Farmakol Toksikol., 51, 57

Cited by

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Related

Authors
Bezuglov, E., Talibov, O., Butovskiy, M., Khaitin, V., Achkasov, E., Waśkiewicz, Z., & Lazarev, A.
Affiliations
  • Sechenov University (RU)
  • Russian University of Medicine (RU)
  • First Pavlov State Medical University of St. Petersburg (RU)
Corresponding author
Lazarev, Artemii
ORCID
Venue
Asian Journal of Sports Medicine
Publisher
Brieflands
Published
2021-02-25
Volume
12
Issue
2
ISSN
  • 2008-000X (ISSN-L)
  • 2008-7209
DOI
10.5812/asjsm.110753
OpenAlex
W3135347726
Semantic Scholar
288d1c8f3c0f85b99082e97878bbf33ee0ea60e3
Cited by
26
References
60
Citations by year
2024: 17 · 2023: 5 · 2022: 3 · 2021: 1
FWCI
1.25
Type
journal article
Language
en
Open access
Licence
Locations
Asian Journal of Sports Medicine (publishedVersion, cc-by-nc)
Topics
  • Social Sciences › Sociology and Political Science › Doping in Sports
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Pharmacological Effects and Assays
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Sports Performance and Training
Keywords
WADA prohibited list, doping in sport, meldonium, trimetazidine, xenon, cobalt, 20-hydroxyecdysone, performance-enhancing drugs, over-the-counter availability

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