Navigating the WADA prohibited list: catchalls and consistencies

Published 04 May 2013 By: Dr Ben Koh, Philip Gibbs

Igor Andreev drinking out of bottle

How far should the World Anti-Doping Agency (WADA) prohibited list “catchall” phrases reach in the context of the control of the use of supplements and culturally/ethnically relevant "complementary and alternative medicines" (CAM)?  This article examines the potential inconsistency of the prohibited list, as a universally binding document, and the implications for athletes.


When the Australian Crime Commission (ACC) investigation into links between organised crime and sport report was released in February, it was hailed as the blackest day in Australian sport. From the ACC publication and subsequent media reports, substances involved are said to include “peptides” —inter alia Thymosin β-4 (TB-4), CJC-1295, Ipamorelin— and “horse supplement” γ-Oryzanol.

We will use TB-4 and γ-Oryzanol, as examples, to examine how far the WADA prohibited list “catchall” phrases [e.g. “potential” and “similar biological effect(s)”] should reach in the context of the control of the use of supplements and culturally/ethnically relevant CAM. We will also consider the example of Cordyceps to illustrate the potential inconsistency of WADA’s prohibited list as a universally binding document, creating impending issues of inadvertent doping, in the context of “legal” supplement and CAM use.

What are Thymosin β-4, γ-Oryzanol and Cordyceps?

TB-4

The β-thymosins are a family of peptides (small proteins), one being TB-4. TB-4 occurs naturally in human blood platelets, white blood cells, the thymus gland and the spleen. Because of its naturally high concentration in the human body and its ubiquitous distribution, it is believed to play an important role in cell survival, as well as in the repair and regeneration of damaged tissue.

TB–4 has been demonstrated to be safe for its current and planned uses in humans following consideration by US Food and Drug Administration (FDA) and by the International Conference of Harmonisation and as a result of 23 non-clinical studies.  TB-4 supplements have also been approved by the Romanian Ministry of Health1 and the supplement is readily available over-the-counter in Australia.

To date, TB-4 has not been properly evaluated in a sports context and its performance-enhancing effects are uncertain. TB-4 may have performance-enhancing potential in sport, but this is likely to be possible only through its healing/recovery properties, in a manner similar to the Platelet-Rich Plasma (PRP) treatments. PRP treatment involves the injection of the patient’s own platelets into areas of injury to assist in recovery, a technique which is not currently banned by WADA and has been specifically addressed by the International Olympic Committee. Given TB-4 is a component found in human platelets, it is conceivable that part of the healing process of PRP may be attributed to TB-4.

γ-Oryzanol

γ-Oryzanol is a substance extracted from rice bran oil, wheat bran and some fruits and vegetables. It has been used in CAM in the treatment of high cholesterol, symptoms of menopause and aging, mild anxiety and stomach upsets2. Although it is used in sports to purportedly increase testosterone and growth hormone (GH) levels, as well as improving strength during resistance exercise training, there is insufficient evidence at this time to quantify its effect on hormone levels. Animal studies have suggested that γ-Oryzanol might actually reduce testosterone production3.

 Notwithstanding the lack of coherent evidence to underpin claimed benefits, γ-Oryzanol have been marketed to, and used by, body builders and strength-training athletes in the hope of boosting strength, increasing muscle gain, reducing body fat, speeding recovery and reducing post-exercise soreness4

Cordyceps

Cordyceps is an insect parasitising fungus that lives primarily on the head of the larva of a particular species of moth. It is one of the most prized medicinal herbs in Traditional Chinese Medicine. Cordyceps has been used extensively as a tonic and health food in China and other Asian countries5 and is commonly added to chicken or turtle soup to improve stamina and libido6. Despite being widely known in eastern cultures as a “health food”, there is limited (western) scientific research into the compound. 

Although the western scientific focus regarding Cordyceps has mainly concentrated on its effect on increasing testosterone levels in the body, research reported in Chinese journals (translated by Dr Ben Koh) also suggests that Cordyceps can potentially also modulate GH levels7. While some studies have shown that Cordyceps increases testosterone levels in vivo in mice and rats, the evidence for sports ergogenic effects and impact on testosterone levels in humans is limited8. Interestingly, the infamous Chinese athletics coach, Ma Junren, (his "Ma's family army" of middle and long-distance runners broke a series of world records, but was suspected of doping after blood tests showed abnormal results prior to the Sydney Olympics), consistently insisted that his athletes had used only traditional Chinese tonics of turtle soup and cordyceps9

As previousy stated, scientific understanding of cordyceps is limited, although many bioactive components of Cordyceps have been extracted and tested. These incude cordycepin, cordycepic acid, ergosterol, polysaccharides, nucleosides and the peptide α-aminoisobutyric acid5, 10, 11. Intriguingly, although the compound α-aminoisobutyric acid is rare in nature12, besides being a component uncovered in cordyceps10, 11, it also forms one of the building blocks of ipamorelin, a WADA-prohibited GH releasing peptide 13-15

 

WADA Prohibited List

WADA has been the international governing body that manages the issue of doping in all sports since 1999. The WADA has defined doping in its World Anti-Doping Code (“Code”). Under the Code, a substance or method is prohibited and considered doping if the WADA determines that the substance or method meets any two of the following three criteria (italics for emphasis by the authors of this paper):

  1. Medical or other scientific evidence, pharmacological effect, or experience that the substance or method has the potential to enhance or enhances sport performance. 
  2. Medical or other scientific evidence, pharmacological effect, or experience that the use of the substance or method represents an actual or potential health risk to the athlete.
  3. Determination by the WADA that the use of the substance or method violates the Spirit of Sport as described in the “Introduction to the Code”.

Based on the above criteria, a WADA panel that consists mainly of allopathic medicine practitioners and biomedical scientists produce a prohibited list that includes all illegal performance enhancing substances and methods (PESM) that are considered doping by WADA. The list is updated as often as is necessary, and no less than at least once annually.

One of the criticisms of the prohibited list is that the rationale behind an inclusion/exclusion is not always well defined. Certainly from an empirical/scientific perspective, many PESM inclusions are not evidence-based (i.e. it relies only on its potential). A discussion on this issue is beyond the scope of the current discussion. 

From consultations with researchers in the field, one of the potential reasons for not making clear the underlying reasons for including or excluding a PESM is to prevent athletes from "beating the system". The view is that publishing all the facts about the PESM might create a situation that encourages the use of illegal PESMs by overly competitive athletes searching for every bit of information that is available.  However, the counter-argument is that if the terms of references are not known, the situation may actually encourage a greater risk taking behaviour and more inadvertent doping incidents. Another criticism of the prohibited lists is its “catchall” inclusions.

In the ACC report, TB-4 was deemed to contravene Section S2-5 of the WADA prohibited list. The ACC report states:

“Peptides are classified as a Schedule 2 (S2) prohibited substance on the WADA Prohibited List and are therefore prohibited for use by professional athletes both in and out of competition. Peptides have been a WADA prohibited substance since at least 2008 …”

Looking at the WADA Prohibited List, it states under section S2-5: 

 “S2. PEPTIDE HORMONES, GROWTH FACTORS AND RELATED SUBSTANCES

The following specific substances and their releasing factors are prohibited:

It then goes on to list a number of substances, but TB-4, γ-Oryzanol and cordyceps are not mentioned. Section S2 does, however, contain the “catchall” clause:

“… as well as any other growth factor affecting muscle, tendon or ligament protein synthesis/degradation, vascularisation, energy utilisation, regenerative capacity or fibre type switching and other substances with similar chemical structure or similar biological effect(s) …”

γ-Oryzanol and Cordyceps were not listed in the recent ACC publication —and γ-Oryzanol was only cited in subsequent media reports16— however TB-4, Cordyceps and γ-Oryzanol, if used by athletes, would contravene section S1 and S2 of the WADA Code under the “catchall” criterion of “similar biological effect(s)”.

 

Is it Doping?

The current marriage of medicine and the law creates significant dangers for the athlete, the athlete’s advisers, and for administrators. As will become apparent, there is no seamless interpretation  of the nature of substances, such as CAMs, between WADA, ASADA and the AIS. Is it realistic and fair (assuming that fairness to an individual athlete is a realistic goal under the World Anti-Doping Code) to expect an athlete to be able to safely navigate his way through the minefield of the WADA ‘catch all sections’. The conflict between the need for certainty for athletes and advisors and the necessity for flexibility in anti-doping policy to accommodate changing practices, leaves the athlete, advised, even compelled to use supplements and substances such as CAMs (and culturally nuanced diets), in a perilous position. 

 

Is total abstention the only safe course?

In World Anti–Doping Agency v Jessica Hardy & United States Anti–Doping Agency (CAS 2009/A/1870) the Panel deliberated at length on the necessary steps that an athlete might take to avoid being categorised as having ‘no significant fault or negligence’ with regard to an adverse analytical finding through the ingestion of contaminated supplements. The Panel observed that ‘an athlete can avoid the risks associated with nutritional supplements by simply not taking them’. 

Hardy hadshown good faith efforts ‘to leave no stone unturned’ before ingesting … she made the research and investigation which could be reasonably expected from an informed athlete wishing to avoid risks connected to the use of food supplements

She had, inter alia, conducted personal conversations with the supplement supplier, been advised that the product was independently tested for purity, and consulted with the team nutritionist. As a result, the CAS established that her reduced ban of 12 months was to be maintained. 

However, for the reasons  we consider below, an athlete, taking every conceivable precaution and having carried out extensive research with regard to supplements and “natural foods”, can still unwittingly fall foul of WADA’s Prohibited list and produce an adverse analytical finding.

 

Supplements and Natural Foods

Amino acids and peptides are smaller sized parts of the protein family. Protein supplements are widely available and commonly used by athletes17-22. Proteins are not banned under WADA’s prohibited lists23-28

The issue and consequent difficulty is not the use of peptides or proteins that are banned per se (as implied by the ACC report), but the use of non-listed peptides that may act as secretagogues (a substance that, when introduced into the human body, causes another substance to be secreted): In this case, the substances being secreted by the body are GH and testosterone. The peptides do not themselves cause the effects of GH or testosterone, but they act through the body’s own gland (pituitary or testicles) to produce the hormones, effectively maximizing the body’s own production. 

The implication of Section S2 in the WADA prohibited list is that an athlete who is diligent and wants to check whether, for example, TB-4 is on the banned list, will not be able to find it, and unless he or she knows how the substance acts and accordingly understands that it infringes the ‘catch all clause’ of “similar biological effect(s)” he or she could be placed in jeopardy. 

The Australian Sports Anti-Doping Authority (ASADA) provides an online tool for athletes to check for specific names of substances to see if the substance was banned in sport29. The website provides a good, but less than perfect, resource for athletes. It states "...If you cannot find your search term below, it may not return a result because it is an overseas product, it is a supplement, or it is a new product..." leaving an athlete confronted by a negative search uncertain whether a potential supplement is legal or not in sport. 

By way of illustration, we searched on the website (15 March 2013) for the peptide “CJC-1295” and retrieved information that all routes of administration of the substance are prohibited in- and out-of-competition. However a comparative search for the peptide “Ghrelin” (with a similar function to CJC-1295) returned a negative result. Accordingly an athlete performing a similar search cannot confirm whether a potential new supplement such as Ghrelin is legal or illegal under the WADA Code. To add to the confusion and consequent mischief, there is sometimes also inconsistency between the information provided by Australia’s lead sports institution, the Australian Institute of Sports (AIS), and ASADA’s website. Cordyceps is an example of such a case.

Under the AIS guide to supplementation30, the substance Cordyceps is listed under “Group C: supplements that have little proof of beneficial effects and are not provided to AIS athletes”. Under this category, AIS indicated that it cannot unconditionally state that, “…the substance does not ‘work’…” (emphasis as cited in website) because the current scientific evidence suggests that either the likelihood of benefits of the substance is very small or that any benefits that occur are too small to be useful. 

Accordingly substances in Group C will not be provided to AIS athletes from Australian Sports Commission (ASC) or AIS program budgets or other sources funded by AIS/ASC. Nonetheless if an individual athlete or coach wishes to use a supplement from this category, they may do so providing: they are responsible for payment of this supplement, and any sponsorship arrangements are acknowledged to AIS marketing. This means that the AIS does not consider the substance Cordyceps to be a banned substance under the WADA Code. 

The ASADA website is less certain in explaining the legality of Cordyceps. When the item Cordyceps was searched online (dated 15 March 2013), the result on the ASADA website indicated that it cannot advise on the status of the use of Cordyceps in sport because they are not comprehensively regulated in Australia. Even if an athlete (and their treating medical practitioner) was familiar with the pharmacodynamics of substances and had knowledge of body physiology, the inconsistency between WADA and ASADA (and AIS) in applying the section S2 rule makes it confusing, and an athlete could far too easily and perilously fall into error. 

Furthermore if, as per the rule in Section S2, “growth factor affecting muscle, tendon or ligament protein synthesis/degradation, vascularisation, energy utilisation, regenerative capacity or fibre type switching and other substances with similar chemical structure or similar biological effect(s)” are to be prohibited, then it would seem inconsistent for PRP injections and various amino acids such as arginine, ornithine, glycine and glutamine (all readily available over-the-counter and capable of acting as growth hormone secretagogues) not to be banned under the WADA prohibited list. After all, the criteria for inclusion of prohibited substances is not dependent only on quantifiable scientific level of evidence of performance effect, but, as indicated by the WADA Code 31, on its potential

“…the potentially unhealthy abuse of certain substances without therapeutic justification based on the mistaken belief they enhance performance is certainly contrary to the spirit of sport regardless of whether the expectation of performance enhancement is realistic…” (p.33)

Athletes and their advisers have always sought an edge. The pursuit of the ultimate level of performance defines their existence. That pursuit must always remain on the legitimate side of the ethical line, a line that must be clearly identifiable and understood by all protagonists. However if headlines such as ‘the blackest day’ are to be avoided in future, then a cohesive, rigorous and culturally inclusive approach to supplement use is needed to separate the ‘cheat’ from the ‘misguided or ill advised’. 


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Author

Dr Ben Koh

Dr Ben Koh is a medical doctor with a Masters in Sports Medicine and a Masters in Psychology and has clinical and educational training in surgery, sports medicine, emergency medicine and critical care.

Philip Gibbs

Philip Gibbs

Philip is a barrister with over 20 years call specialising in Crime and Sports Law. Philip was recently co – counsel at the Court of Arbitration for Sport acting for Taekwondo Olympic gold medallist Mu Yen Chu and Chinese Taipei against the International Olympic Committee.