The WADA Prohibited List has historically proven to be both a guide and temptation for formulators when considering what ingredients to use in sports nutrition products. As a guide, it outlines what substances people should stay away from. As a temptation, the confines of the WADA Prohibited List can create opportunities for products to exploit holes in the language or target effects that are banned with ingredients that are not. Dealing with the blurred lines between banned substances and sports nutrition is complex as examples from the past, present and future demonstrate.
The nexus of the challenge is in the effects that are both prohibited in sport but sought after in sports nutrition. Muscle building, weight loss, energy stimulation, myostatin or aromatase inhibition, and estrogen blocking are all banned categories and also targeted effects in sports nutrition. Some substances may be prohibited not by name but by interpretation. The practical application of sport drug testing ultimately determines what is prohibited and what is not.
The perfect example of this phenomenon was demonstrated with the prevalence of designer steroids, or prohormones, in the dietary supplement realm more than a decade ago. The 2010 WADA Prohibited List covered anabolic agents with 46 steroids and another 21 naturally present steroids or metabolites included by name. Many alternatives were outlined in the infamous Julius A. Vida’s “Androgens and Anabolic Agents,” published in 1969, which reviewed 666 compounds that had been evaluated during the heyday of anabolic steroids research. The US$775 price tag attests to its value still today.
Methasterone, also known as Superdrol, was one of only a handful of designer steroids on the 2010 WADA Prohibited List leaving many others to be exploited in the marketplace as alternatives. In fact, the 2020 WADA Prohibited List still does not include the majority of the 24 designer steroids included in the Designer Anabolic Steroid Control Act of 2014 (DASCA), which after two previous congressional attempts in 1990 and 2004 was the final piece of legislation that put a nail in the coffin for the prohormone marketplace.
“The 2014 law also introduced a novel basis upon which certain drugs or hormonal substances could be classified as anabolic steroids,” noted sports nutrition lawyer Rick Collins. “The law permits the mere marketing or promotion of the substance as a muscle-builder to be an alternative to scientific evidence about its muscle-building effects.”
Methasterone was exposed in the Washington Post in 2005, thanks to the scientific work of my father, Dr. Don Catlin, and his team who unveiled five designer steroids in dietary supplements the Post sent for analysis. Methasterone is found on page 87 of Vida’s Guide. Methydiazirinol continued to be a popular alternative until 2014. It is found on page 90 of Vida’s Guide but it is not found by name on either the 2020 WADA Prohibited List or the list of designer steroids included in the 2014 DASCA. This substance had been flying under the radar. The gaps between what the WADA list or the Anabolic Steroid Control Act iterations included is what was filled by designer steroid supplements for years.
When the prohormone party ended a new category of banned substance had developed as an attractive alternative, namely SARMs, or selective androgen receptor modulators. These were not addressed by the prohormone regulations and began to proliferate in their stead. SARMs were banned in sport beginning with the 2008 WADA Prohibited List, which included SARMs in general with no examples. It was not until 2015 that examples were added and then only two appeared, andarine and ostarine. The 2020 WADA Prohibited List now includes four with LGD-4033 and RAD 140 added.
In November 2019 the SARMs Control Act was introduced to address the growing concern that these drugs—in various stages of clinical research and none of which have been approved by FDA—had become popular as illegal dietary supplements. The act lists nine specific compounds that qualify. On the BSCG website we have a list of 15 on our Dietary Supplement Ingredient Advisory List that have been found on the market. The gaps in examples over the years allowed unscrupulous formulators to key in on ingredients that qualified as SARMs but were not yet on the radar of authorities.
Prohormones and SARMs were both categories of drugs that were exploited in the nutrition realm over the years in the form of illegal supplement products. But when it comes to weight loss, energy, myostatin and aromatase inhibition, or estrogen blocking, the lines between banned substances and supplements gets quite fuzzy. This is because these supplement categories often rely on an array of legitimate natural products that may have effects that could be interpreted as prohibited but are not banned in practice. Meaning these would not be expected to cause positive drug tests since most are not targeted in sport drug testing.
The infamous supplement ingredient DMAA, or methylhexaneamine, is the perfect example of the natural product dilemma that arose in the arena of pre-workout and weight loss products, which often turn to stimulants for efficacy. DMAA was suggested to be geranium oil extract, and as such it grew to enormous popularity in products like USP Labs’ Jack3D, which generated hundreds of millions in sales. Eventually the product was involved in one of the largest FDA lawsuits ever in the nutrition industry. DMAA has been implicated in some serious adverse events and has been the subject of numerous class action lawsuits.
DMAA became popular around 2006. In 2008 and 2009 the first positive drug tests for DMAA occurred before it was actually added to the WADA Prohibited List. WADA executed the little-used but available clause that prohibits substances with “a similar chemical structure or similar biological effect(s),” which makes the list language somewhat infinite. Methylhexaneamine was not added to the WADA Prohibited List until 2010.
Once it was prohibited a number of alternatives popped up in its place including DMBA, which was popularized as AMP Citrate and suggested to be Pouchong tea extract, and DMHA, which was popularized as Octodrine and suggested to be from Kigelia africana extract or other natural sources. These compounds were not added to the WADA list for several more years.
Regulators played whack-a-mole as formulators dabbled with these compounds and others. Ultimately, with the natural origin of these compounds in doubt their legitimacy as ingredients was questioned as they did not appear to qualify under the definition of a dietary supplement included in the Dietary Supplement Health and Education Act (DSHEA) or similar language in other countries.
Today there are categories like myostatin inhibitors, aromatase inhibitors and estrogen management supplements that could be interpreted as prohibited based on their potential effects according to a strict reading of the WADA Prohibited List language. Yet many of these substances are common supplement ingredients and would be benign when it comes to a drug test.
Myostatin inhibitors were first added to the WADA Prohibited List in 2008 but, as was the case with SARMs, no examples were provided, leaving it open as to what might qualify. Epicatechins that come from green tea extract have been demonstrated to be myostatin inhibitors and are sold as such in products like Epicat. The research suggests, “epicatechin decreases myostatin.” Yet while they may be prohibited in effect, in practice epicatechin is not a focus of sport drug testing, at least not yet.
Follistatin was added as an example of a myostatin inhibitor on the 2019 WADA Prohibited List. Follistatin can be found in eggs and the literature notes it, “has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength.” Ironically, there is an egg-derived follistatin-based supplement that is certified for sport today. The maker touts its effectiveness as a natural myostatin reducing agent. In practice, there is no test for follistatin currently employed in sport drug testing so this substance seems to fall into a unique category of a naturally derived substance that is prohibited but does not yet result in positive drug tests.
We end with aromatase inhibitors and estrogen blockers, which are important medicines in cancer treatment where natural alternatives are also commonly explored. These two categories have been prohibited by WADA for decades. The substances listed by name are known pharmaceutical drugs that have been used in medicine. There are no natural products listed in either category but there are many that could qualify based on their effects.
A 2008 publication on “Natural Products as Aromatase Inhibitors” notes that “nearly 300 natural product compounds have been evaluated for their ability to inhibit aromatase.” Some of the more effective examples are white button mushrooms and grape seed extract. Common families of compounds like alkaloids, catechins, flavones, fatty acids, terpenoids and more have been examined as aromatase inhibitors.
Many of these compounds are common in supplement ingredients like apigenin (present in high amounts in chamomile), epigallocatechin gallate (EGCG, the most abundant catechin in tea), hesperidin (found in citrus), isoflavones (common in beans), eicosapentaenoic acid (EPA, a targeted fatty acid in fish oils), ursolic acid (in apple peels and rosemary), and resveratrol (found in the skin of grapes and berries). None of these would be expected to cause a positive drug test even though their potential as aromatase inhibitors may qualify them as banned according to the WADA Prohibited List language.
In the realm of estrogen management, again a variety of natural products may qualify. Publications have explored this topic too including one focused on “Natural Products for the Management and Prevention of Breast Cancer.” This paper examines the effects of 3,3′-Diindolylmethane (DIM), found in cruciferous vegetables like broccoli, cauliflower and cabbage, along with tamoxifen, a pharmaceutical selective estrogen receptor modulator on the WADA Prohibited List. It notes that “in randomized, placebo-controlled trial studies, DIM significantly increased the chemosensitivity of tamoxifen and showed favorable effect on estrogen metabolism.” DIM is a legitimate supplement ingredient and it is not on the WADA Prohibited List nor is it targeted in drug testing.
As the WADA Prohibited List continues to grow and consider new substances for addition the natural product industry should take heed. In an interesting move, WADA added ecdysterone to the 2020 Monitoring Program. This means they are now testing for it and considering it for future listing. As an article in MedicalNewsToday.com notes, “Ecdysterone is the main compound in spinach extract.”
Ecdysterone is one of many ecdysteroids, which are found in “about 6% of plants in existence,” according to Examine.com. A number of them have been explored for their potential to have bioactivity similar to testosterone. This is likely why WADA has become interested in ecdysterone. Indeed a publication in 2019 highlighted a possible concern with ecdysterone and suggested it be added to the WADA Prohibited List. Whether this may extend to other ecdysteroids in the future is yet to be seen.
Pay attention as the WADA Prohibited List evolves, as benign ingredients like spinach extract are now under the organization’s watchful eye. Historical examples have demonstrated that natural products may be considered for inclusion on the list along with pharmaceutical agents. As the lines between prohibited substances in sport and natural products get more hazy, formulators need to be wary about what they use in nutrition products, as do athletes or other drug-tested professionals like first responders or military officers.
One good way for both formulators and drug-tested professionals to protect themselves from these real world concerns is to look for third-party certification programs focused on banned substances that offer built-in security. This can take the guesswork out of the equation for brands and consumers and help both make responsible choices when it comes to supplements and related products.
Oliver Catlin is the president and co-founder of BSCG (Banned Substances Control Group), an international third-party certification and testing provider. With a background in sports anti-doping, he is widely regarded as a thought leader in the field of sports nutrition and dietary supplements.