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2019 WADA Prohibited List Summary of Major Modifications and Explanatory Notes

New Year Predicament: Follistatin Now Both a WADA Prohibited Substance and a Supplement Certified for Sport

January 8, 2019

Yolked Supplement Contains Follistatin, a Myostatin Inhibitor

With the onset of 2019, a new WADA Prohibited List has taken effect. The new myostatin inhibitor language is perhaps the most significant change and has great potential impact on the nutrition and sport drug-testing industries, as we discussed in depth in October. Agents that may reduce myostatin expression are now considered banned, including specifically follistatin. Follistatin may be both prohibited and perhaps recommended in the form of a dietary supplement that is certified as safe for athletes. Other popular supplement ingredients that contain epicatechins, like green tea extract or cocoa extract, may also be interpreted as prohibited myostatin inhibitors.

2019 WADA Prohibited List Summary of Major Modifications and Explanatory Notes

2019 WADA Prohibited List Summary of Major Modifications and Explanatory Notes – Excerpt S4

The dilemma specific to myostatin inhibitors confronts athletes, nutritionists, third-party dietary supplement certification programs, and anti-doping policy makers. It demonstrates how difficult it can be to interpret what does or doesn’t qualify as a prohibited substance.

To understand this predicament, one must review the WADA Prohibited List language for myostatin inhibitors. Myostatin inhibitors are included under the primary category “S4 Hormone and Metabolic Modulators.” The 2018 WADA Prohibited List language for S4.4 read as follows: “Agents modifying myostatin function(s) including, but not limited, to: myostatin inhibitors.” The 2019 WADA Prohibited List language under S4.4 has been expanded and clarified below.

Agents preventing activin receptor IIB activation including, but not limited, to:
Activin A-neutralizing antibodies;
Activin receptor IIB competitors such as: Decoy activin receptors (e.g. ACE-031);
Anti-activin receptor IIB antibodies (e.g. bimagrumab);
Myostatin inhibitors such as: Agents reducing or ablating myostatin expression; Myostatin-binding proteins (e.g. follistatin, myostatin propeptide); Myostatin-neutralizing antibodies (e.g. domagrozumab, landogrozumab, stamulumab).

The previous language required an interpretation that follistatin would qualify as an agent that could modify the function of myostatin. The new language specifically prohibits follistatin and also potentially includes anything that could reduce myostatin, depending on interpretation.

Follistatin, which is present in fertilized chicken embryos, is now used as a supplement ingredient. Other compounds like epicatechin, common in the nutrition industry in the form of green tea extract and cocoa extra, have been studied as potential myostatin inhibitors. It is unknown whether epicatechin will be considered prohibited so that question remains open for consideration, but not so with follistatin.

The specific prohibition of follistatin presents another dichotomy. In April of last year, Myos Rens announced that their Yolked ™ supplement was NSF Certified for Sport ®.  NSF’s supplement certification program is recommended by a number of sport organizations subject to drug testing, according to NSF’s website. [1] NSF’s online database shows that the Yolked ™ product is currently NSF Certified for Sport ®. The primary ingredient in Yolked ™ is Fortetropin ®, which consists of follistatin. Follistatin is now specifically prohibited by the 2019 WADA Prohibited List, but because it is certified it may also be inadvertently recommended by sporting organizations or considered approved by athletes.

Yolked - NSF Certified for Sport Listing - 2019-01-08

Yolked – NSF Certified for Sport ® Listing – 2019-01-08

Since not all sport leagues or organizations adopt the WADA Prohibited List language as written, it is worth exploring further to see how myostatin inhibitors, follistatin, or other potential myostatin reducing agents may be treated across various groups. The answer depends on how the language in the respective prohibited substance lists is interpreted.

CCES: The Canadian Centre for Ethics in Sports was “born out of a landmark merger between the Canadian Centre for Drug-Free Sport and Fair Play Canada,” according to its website. It works “for, and on behalf of athletes, players, coaches, parents, officials and administrators.” CCES accepts the WADA Prohibited List language as written and communicates it to Canadian athletes.

CFL: The Canadian Football League Prohibited Substances List is available for download. The list includes a category for “Hormone and Metabolic Modulators,” the same category WADA places myostatin inhibitors. The CFL list, however, does not specifically mention myostatin inhibitors, nor does it include related substance language for the category. So, myostatin inhibitors may not be prohibited in general, and it is not clear how follistatin or other potential reducing agents would be treated.

CPSDA: The Collegiate and Professional Sports Dietitians Association is an independent not-for-profit organization. The CPSDA statement of purpose indicates that the “Collegiate and Professional Sports Dietitians Association (CPSDA) represents the vast majority of advanced practice registered dietitians in the United States who work full-time with athletes in colleges, professional sports, Olympic training centers, the U.S. Military and in law enforcement.” The prohibited list of relevance to CPSDA members depends on who they work with; for some, myostatin inhibitors like follistatin are clearly prohibited, while for others they may appear to be recommended or approved in the form of the Yolked supplement.

LPGA: The Ladies Professional Golf Association 2018 LPGA Prohibited Substances list includes “Hormone and Metabolic Modulators” with sub-item 4 covering “Agents modifying myostatin function(s) including, but not limited, to: myostatin inhibitors.” This language is the same as the 2018 WADA Prohibited List. The 2019 LPGA list does not seem to be available yet so it is not known how follistatin will be treated. If the LPGA follows the WADA changes, follistatin and other mysotatin reducing agents will be prohibited.

MLB: Major League Baseball provides the MLB Prohibited Substances List online, which remains relevant through 2021. It includes “Myostatin Inhibitors” under number 68. No examples are provided. If WADA now interprets follistatin to be a specific example of a myostatin inhibitor, MLB should also interpret follistatin or other reducing agents as prohibited–but this is not clear.

NCAA: The National Collegiate Athletic Association 2018-19 NCAA Banned Drugs list is not an exhaustive list and only includes examples of drugs in certain banned categories. Category “f Peptide Hormones and Analogues” is included with examples listed coming from the similar WADA category S2. There is no category, however, for Hormone and Metabolic Modulators wherein WADA includes myostatin inhibitors. It is uncertain whether follistatin or other myostatin inhibitors would be banned in the NCAA.

NFL: The National Football League List of Prohibited Substances includes a category for “Protein and Peptide Hormones” but does not include language indicating that “other substances with a similar chemical structure and similar biological effect(s)” may be prohibited. The list is specific and myostatin inhibitors do not appear to be included. The NFL does ban “gene doping,” and in that section they include compounds from WADA category S4.5 Metabolic Modulators, but none from category S4.4 where myostatin inhibitors are listed. Since the injection of follistatin AAV1-FS344 may be considered gene doping, it is possible follistatin in one form could be interpreted as prohibited but myostatin inhibitors or their reducing agents do not appear to be covered in general.

NHL: The National Hockey League list of prohibited substances is not available to the public. A note on NHL.com reads as follows: “The joint Committee… will agree on a Prohibited Substances List. The list will include performance-enhancing substances on the list maintained by the World Anti-Doping Agency (WADA) for both in-competition and out-of-competition testing.” It does not clarify that all WADA Prohibited Substances are banned. So, it is possible that the new 2019 WADA Prohibited List language for myostatin inhibitors would be relevant within the NHL but this is uncertain.

PGA: The Professional Golf Association publishes the PGA Tour Anti-Doping Manual online. Myostatin inhibitors are included under section 4.4: “Agents modifying myostatin function(s) including, but not limited, to: myostatin inhibitors.” Like the LPGA, the PGA Tour language is the same as the 2018 WADA Prohibited List. It is likely the 2019 WADA Prohibited List changes will apply in the PGA as well but like the LPGA the 2019 Prohibited List does not seem to be available yet.

Consideration of follistatin, and myostatin inhibitors in general, as prohibited substances in sport reveals surprising dilemmas that need to be addressed and resolved. This review demonstrates the extraordinary complexities faced when trying to set or interpret the confines of anti-doping policy. In these modern times you would think the outlines of prohibited substances would be consistent but that does not seem to be the case with follistatin, or myostatin inhibitors in general.

We believe there should be consistency in prohibited substance list language, so that predicaments like these can be avoided. In our earlier blog post, BSCG suggested possible prohibited list language adjustments to address concerns over follistatin and other myostatin inhibitors. Hopefully the sporting community will consider and implement workable solutions soon as athletes and other professionals deserve clarity as to what does or doesn’t qualify as a prohibited substance.

Oliver Catlin
BSCG President

[1] The NSF Certified for Sport® website includes the following on its homepage:

NSF International’s Certified for Sport® helps athletes make safer decisions when choosing sports supplements. MLB, NHL and CFL clubs are permitted to provide and recommend only products that are Certified for Sport®. Certified for Sport® is also recommended by the NFL, PGA, LPGA, CCES, CPSDA, Taylor Hooton Foundation and many other sports organizations.

Follistatin Prohibited in Sport

2019 WADA Prohibited List Bans Follistatin – Possibly Eggs, Green Tea, and Chocolate

October 25, 2018

Follistatin and Epicatechin could be Prohibited in Sport as Myostatin Inhibitors

Myostatin inhibitors are of growing importance for anti-doping authorities to consider as this category is expanding and presenting new potential doping agents. Recognizing that reality, the World Anti-Doping Agency (WADA) has included in its 2019 WADA Prohibited List adjusted language for the category as summarized in the 2019 Summary of Major Modifications and Explanatory Notes. WADA and other sporting groups may not be fully aware of the ramifications this change could have within the nutrition realm. The potential impact on Olympic and professional sport drug-testing policy and the dietary supplement or other nutrition products athletes may elect to consume is astounding.

First, take a look at the language used in the WADA Prohibited List for myostatin inhibitors. Myostatin inhibitors are included under the primary category “S4 Hormone and Metabolic Modulators.” The 2018 WADA Prohibited List language for S4.4 reads as follows: “Agents modifying myostatin function(s) including, but not limited, to: myostatin inhibitors.” The new expanded 2019 WADA Prohibited List language under S4.4 is noted below.

Agents preventing activin receptor IIB activation including, but not limited, to:
Activin A-neutralizing antibodies;
Activin receptor IIB competitors such as: Decoy activin receptors (e.g. ACE-031);
Anti-activin receptor IIB antibodies (e.g. bimagrumab);
Myostatin inhibitors such as: Agents reducing or ablating myostatin expression; Myostatin-binding proteins (e.g. follistatin, myostatin propeptide); Myostatin-neutralizing antibodies (e.g. domagrozumab, landogrozumab, stamulumab).

Two significant changes are of primary importance to the dietary supplement and functional food industries and the athletes that use such products. The first is the inclusion specifically of “agents reducing or ablating myostatin expression,” and the second is the addition of “follistatin” to the list.

Green tea - EpicatechinThe first change suggests that anything that may reduce myostatin levels could be considered prohibited. Flavonoids present in plants may fit this description. An article from The Journal of Nutritional Biochemistry found that treatment with the flavanol epicatechin, “significantly decreases myostatin levels…, while follistatin increases.” Two particularly rich sources of epicatechin consumed in the diet are green tea and chocolate, particularly dark chocolate. Both are often used as supplement ingredients in the form of green tea extract and cocoa extract. It is unclear whether these common items would be interpreted as prohibited since they are not actually listed, but it seems they could be.

There is no question as to whether follistatin is prohibited as now it is specifically enumerated on the 2019 WADA Prohibited List. Its prohibition is likely due to the potential for it to be injected as a gene-doping agent in the form of AAV1-FS344 from Milo Biotechnology. A journal article in Science Translational Medicine from 2009, “Follistatin gene delivery enhances muscle growth and strength in nonhuman primates,” describes how this works.

In simple terms follistatin in the form of FS344 is attached to an inactive virus, AAV1, and then injected into muscle seeking to inspire the body to replicate follistatin. Information on injection protocols for AAV1-FS344 can be found on various message boards and it is also discussed on Reddit.

There are different numbered forms of follistatin, including FS288, FS300, FS315 and FS344. The number represents the amino acid count. The name follistatin alludes to the protein’s action to suppress follicle-stimulating hormone (FSH). A 2009 article in Muscle & Nerve notes that “follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength.”

Follistatin - Myostatin InhibitorsFollistatin can be found commonly in the food supply in egg yolks. Fertilized egg yolks are particularly high in follistatin levels. Fertilized egg yolk derived products have been created and patented for use as dietary supplement ingredients including one called Fortetropin®, formerly known as Myo-T12.

Research studies have considered Fortetropin® and its potential to reduce myostatin or impact muscle growth including one in the Journal of the International Society of Sports Nutrition entitled, “The effects of a myostatin inhibitor on lean body mass, strength, and power in resistance trained males.” This study notes that Myo-T12 “is follistatin derived from fertile chicken egg yolk isolate.” An information sheet available from the company Myos Rens that owns Fortetropin® notes that it “reduces free serum myostatin levels.” This sheet alludes to a midterm opportunity where the ingredient could be used as a medical food for dietary management of sarcopenia and cachexia, conditions that lead to muscle loss.

On April 10, Myos Rens announced that their Yolked™ supplement attained NSF Certified for Sport® status. The primary ingredient in Yolked™ is Fortetropin®. The NSF Certified for Sport® homepage notes, “MLB, NHL and CFL clubs are permitted to provide and recommend only products that are Certified for Sport®. Certified for Sport® is also recommended by the NFL, PGA, LPGA, CCES, CPSDA, Taylor Hooton Foundation and many other sports organizations.”

Recommendation of a dietary supplement certification program equates to tacit endorsement of products that are certified and conveys to the athletes or constituents that products are acceptable to use. In this example, a substance like follistatin may be both prohibited and also recommended at the same time, demonstrating the conflicts of interest and confusing realities that can result. Surely this was not the intent of any of the groups involved.

It should be noted that the U.S. Anti-Doping Agency (USADA) does not recommend any specific third-party certification program for banned substances but rather teaches athletes to reduce their risks by considering third-party certified products if they elect to use supplements. USADA advises athletes to, “Look for third-party certification, but also evaluate the limits of each program. No program is perfect, and certification is not a guarantee that the product is safe or free from prohibited substances.” USADA provides good supplement education materials through their Supplement411 site.

Digging deeper, we see variations in prohibited substances list language across organizations creates inconsistency in what may be considered banned. A review of drug-testing policies and prohibited substances lists across ten groups reveals that only 50-80% appear to specifically prohibit myostatin inhibitors or agents that may reduce myostatin expression like follistatin. The difference in prohibition considerations for myostatin inhibitors, or what might qualify as such, demonstrates the challenges and complexities all groups face when trying to outline, or operate within, the confines of anti-doping policy.

So, is follistatin even detectable, you might ask? The answer is yes but the methodology is young. In order to be effectively applied, a threshold will be necessary to exclude impacts from follistatin that may be present in the diet. There does not yet appear to be a threshold considered in the WADA system. Perhaps it will be possible to differentiate FS344 generated in the course of gene doping from other forms of follistatin that may be naturally present?

Research may provide some answers. A project funded by the Partnership for Clean Competition (PCC) began in 2015 and remains in progress focused on “Developing a detection signature for current and prior follistatin gene doping.” The PCC is a partnership that includes MLB, NFL, NHL, PGA, and USADA.

The far-reaching implications the WADA Prohibited Substances List language has on banned substance policies elsewhere or within the nutrition industry must be considered when making changes. Realities presented by compounds present in our food supply must be evaluated and the language tailored to appropriately prohibit drugs of concern but not food or nutrition ingredients.

Epicatechins, Chocolate - Myostatin InhibitorsIt was likely WADA’s intention with the recent change to prohibit injectable follistatin AAV1-FS344 as a gene-doping agent; not green tea, chocolate or eggs. If follistatin is worthy of prohibition in general, then what should the allowable level be? The addition of drugs that act as myostatin-reducing agents is laudable, but the language as written could also be interpreted to include food items. WADA, or other groups that may consider their prohibited list language, could clarify their intentions and also carve out protection for the food and nutrition industry with some simple adjustments.

Consider the following possible clarifications related to mysotatin inhibitors. Adding the word ‘pharmaceutical’ in front of myostatin inhibitors and agents reducing or ablating myostatin expression would make it clear the category is targeting drugs not foodstuffs. If follistatin AAV1-FS344 injections are the target, why not clarify with one of the following: ‘follistatin AAV1-FS344’ or ‘follistatin injections.’

Consistency and clarity in the banned substance language is essential in order for constituents to understand what is or is not acceptable. In the case of myostatin inhibitors, this is clearly in need of improvement. When in some realms items that may qualify as prohibited are inadvertently endorsed, and basic food items may qualify as banned, it is time for sports and anti-doping authorities, nutrition industry experts, and certification providers to unite in resolution of such issues. Athletes and others that rely on transparency in drug-testing policy deserve nothing less.

– By Oliver Catlin

Special thanks to Joseph Taylor for editing support and to Susan M. Kleiner, PhD, RD, FACN, CNS, FISSN for serving as an external expert reviewer.

Field of Hemp - CBD

Demystifying Hemp, CBD, Cannabis and Marijuana and Considerations on Regulations

October 13, 2018

Industrial hemp-derived oils and other products, commonly referred to as cannabidiol (CBD) products, have grown popular with general consumers and athletes, posing a number of legal, regulatory and consumer questions. Here, we aim to demystify hemp and cannabidiol, or CBD, and evaluate the considerations on whether CBD should be categorized as a drug or a dietary supplement. We invite you to explore the realm of hemp, CBD, Cannabis and Marijuana and considerations on regulations in depth.

Distinctions between Cannabis and Marijuana

Cannabis Three SpeciesThe explanation starts with marijuana. Marijuana has been vilified by many, while also being utilized by others, for hundreds of years. Marijuana is not a scientific term for the plant but rather the general nomenclature typically used for the psychoactive form of cannabis known for getting people high. Cannabis is the more correct general term for the plant, which applies to the cannabis genus in the cannabaceae family, which is part of the plant kingdom. There are three primary species: sativa, indica, and ruderalis. Many hybrid species have developed over the years.

Section 812 of the Controlled Substances Act (21 U.S.C. §801 et seq.) (CSA) lists substances which were controlled in 1970 when the legislation was initiated. Substances may be added, removed, or transferred between schedules annually. The U.S. Department of Justice Drug Enforcement Agency (DEA) Diversion Control Division manages the list of controlled substances. The list includes ‘Marihuana’ and ‘Marihuana extract’ with ‘cannabis’ and ‘marijuana’ also noted. These are all categorized under Schedule I the strictest category of control. Other countries categorize and treat the cannabis plant differently around the world, but we focus here on the state of affairs in the United States.

Phytocannabinoids (Cannabinoids for short) Naturally Present in Cannabis

To understand the world of cannabis one must have a simple understanding of the chemistry of the plant. Delta 9-Tetrahydrocannabinol (D9-THC) is the most notorious of the phytocannabinoids naturally present in cannabis and is the primary chemical responsible for the psychoactive effects. It is this compound, not the cannabis plant, which should be the focus of regulations.

Hundreds of phytocannabinoids are naturally present in cannabis with the following frequently discussed along with D9-THC: Cannabidiol (CBD), Cannabidiolic Acid (CBDA), Cannabigerol, (CBG), Cannabinol (CBN), Delta 8-Tetrahydrocannabinol (D8-THC), Cannabichromene (CBC), Tetrahydrocannabinolic Acid (THCA). CBD has become the focus of much attention and study for its potential health benefits or possibilities for use as medicine. The other natural phytocannabinoids may also have potential utility.

Health Benefits vs. Drug Efficacy

Potential health benefits and possible utility as a medicine should not be confused with one another. Dietary supplements and natural products may have potential health benefits while substances that qualify as drugs must have a refined consistent production process and proven medical efficacy for a specific purpose. This distinction needs to be realized when considering the categorization of hemp-derived oil products, also known as CBD products.

Hemp, Hemp Species, and Historical Use of Cannabis

OK, what is hemp? Hemp in simple terms is a cannabis plant bred and grown to be low in the psychoactive D9-THC. The legal description of industrial hemp in the U.S. mentions cannabis sativa L., but other species of cannabis could also be bred to be below the 0.3 percent D9-THC limit outlined, and high in CBD. Cannabis sativa L is included in the definition of legal hemp as that species historically has a growth pattern more conducive to the production of fiber or seed products. When it comes to the production of hemp with a focus on CBD, other cannabis species may also have relevance.

Hemp itself has been grown for centuries for use in industrial products like rope, paper, seed, food protein, and more. Hemp cultivation has evolved more recently to focus on producing plants that are high in CBD. The historical use of cannabis resins or oils in edible form can be traced back thousands of years to traditional Chinese medicine and other forms of cultural medicine, an important consideration in the proper categorization of hemp-derived products.

Field of Hemp - CBD

Current U.S. Hemp Regulations

So, how has industrial hemp been defined and outlined for use in the U.S.? Two codes apply, one that is current, and the Hemp Farming Act of 2018 introduced in April 2018 by Senator Mitch McConnell from Kentucky that is pending.

U.S. Code – Title 7 – Chapter 88 – Subchapter VII – § 5940 is current. This code establishes the legal confines under which hemp can be legal cultivated. To further demystify the category, we must start with this important statute as written. Important terms are highlighted with italics:

(a) In General – Notwithstanding the Controlled Substances Act (21 U.S.C. 801 et seq.), chapter 81 of title 41, or any other Federal law, an institution of higher education (as defined in section 1001 of title 20) or a State department of agriculture may grow or cultivate industrial hemp if—

(1) the industrial hemp is grown or cultivated for purposes of research conducted under an agricultural pilot program or other agricultural or academic research; and
(2) the growing or cultivating of industrial hemp is allowed under the laws of the State in which such institution of higher education or State department of agriculture is located and such research occurs.

(b) Definitions
In this section:

(1) Agricultural pilot program – The term “agricultural pilot program” means a pilot program to study the growth, cultivation, or marketing of industrial hemp

(A) in States that permit the growth or cultivation of industrial hemp under the laws of the State; and
(B) in a manner that—

(i) ensures that only institutions of higher education and State departments of agriculture are used to grow or cultivate industrial hemp;

(ii) requires that sites used for growing or cultivating industrial hemp in a State be certified by, and registered with, the State department of agriculture; and

(iii) authorizes State departments of agriculture to promulgate regulations to carry out the pilot program in the States in accordance with the purposes of this section.

(2) Industrial hemp
The term “industrial hemp” means the plant Cannabis sativa L. and any part of such plant, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.

(3) State department of agriculture

The term “State department of agriculture” means the agency, commission, or department of a State government responsible for agriculture within the State.

Industrial Hemp Products and Commerce Under Current U.S. Regulations

So industrial hemp has been legal to cultivate for research purposes including marketing. Some people might argue marketing equates to sales, but that has been an important element in need of clarification.  Under current regulations, cultivation is subject to states permitting the growth of industrial hemp and to the growth occurring at state-registered department of agriculture sites or institutions of higher learning. As of 2018, more than 38 states allow hemp cultivation for commercial, research or pilot program purposes.

The tight set of requirements outlining ‘legal’ hemp cultivation has likely been abused as the industrial hemp product industry has exploded and perhaps co-mingled with the medical and recreational marijuana industries. When it comes to the rules of commerce for the burgeoning industrial hemp oil product industry enormous questions remain.

Nonetheless, a multi-billion dollar industrial hemp oil industry has emerged over the last decade. The terminology used has been a primary challenge. The product sold is industrial hemp oil but the category has been marketed and referred to broadly in commercial practice as the ‘CBD product’ industry. The distinction between industrial hemp oil and ‘CBD products’ must be made in order for clarification of the legality and regulations of this industry.

The industry has expanded based on the notion that ‘CBD products’ may qualify as dietary supplements and could be sold legally across state lines. This is a central component of the debate that we will return to later. The FDA has reiterated, as has the DEA, that sales of ‘CBD products’ or industrial hemp oil products are still considered illegal according to their written regulations. Of course in each state individual laws may also apply. Many states have also questioned the legality of the sale of ‘CBD products’ and industrial hemp oil, including California. Industrial hemp oil has proven hard to categorize due to the terminology challenge.

The enforcement of the regulations has temporarily reached a stalemate and seems to be focused only on those companies that make inappropriate medical claims regarding the benefit of ‘CBD products.’

New Hemp Farming Act of 2018 Proposes Changes in the Treatment of Hemp

What does the new Hemp Farming Act of 2018 attempt to do? The important elements are summarized in the discussion below.

First, it clarifies the definition of hemp to specifically include extracts and other cannabinoids as follows: “(1) HEMP.—The term ‘hemp’ means the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.” This is important as the current language implies that extracts, oils and cannabinoids would be allowed while the new proposed language specifically includes these items.

Second, it attempts to clarify what sites may be involved in cultivation. It now specifically mentions Native American tribes and has eliminated the specific mention of institutions of higher learning as the current language includes. The Act reiterates that states will be responsible for registering and controlling cultivation sites. It also authorizes the “study of agricultural pilot programs to determine the economic viability of the domestic production and sale of industrial hemp.”

Third, it also allows for important infrastructure like farm insurance to be applied to hemp. Previously cultivation of hemp could not be protected from disaster or other issues like all other industrial crops.

Finally and perhaps most importantly, it proposes to amend the Controlled Substances Act language by clarifying what is controlled. The new proposed language is better but could still use improvement.

Consideration of Controlled Substances Act and Industrial Hemp Definition Language

The Hemp Farming Act of 2018 proposes to clarify the controlled substances list language in several key ways. To summarize, the term marijuana will now exclude hemp, and ‘Tetrahydrocannabinol’ will be added as Schedule 1, while ‘Tetrahydrocannabinols from hemp’ will be excluded.

The term “tetrahydrocannabinols” was clarified by the DEA in 2003 to refer to both natural and synthetic THC. There are problems with the term as it is non-specific as to the reference of other natural phytocannabinoids.

The proposed changes are a good effort to clarify the language but could be improved as follows. The notation of ‘cannabis’ in the list should be removed as it could still refer to hemp.  ‘D9-THC’ should be referenced as the specifically scheduled compound, not ‘tetrahydrocannabinol’, as that term could refer to D8-THC or other phytocannabinoids with ‘tetrahydrocannabinol’ in the name. The listing of ‘tetrahydrocannabinol’ under Schedule I should be replaced with, ‘D9-THC is prohibited in amounts above 0.3% in any product.’ The confusing reference to excluding ‘tetrahydrocannabinols from hemp’ should be replaced with the broader definition ‘phytocannabinoids from hemp.’ ‘Synthetic cannabimimetics’ could be noted to include these important and dangerous compounds. Finally, consideration could be made for expanding the legal definition of industrial hemp to other species of cannabis by simply removing the words ‘sativa L.’ from the definition of industrial hemp.

GW Pharmaceuticals Cannabis-Derived Drugs – Epidiolex and Sativex

The controlled substance list language is important, particularly given the recent FDA approval of GW Pharmaceuticals cannabis-derived drug Epidiolex. The approval of Epidiolex has created even more questions in the debate over whether CBD should be considered a drug or a supplement. So what is Epidiolex, which has been approved for the treatment of seizures, and its cousin Sativex, which is in clinical trials for spasticity?

Epidiolex (cannabidiol, CBD) is described at Epidiolex.com as follows: “EPIDIOLEX contains highly purified, plant-derived cannabidiol; the active ingredient is nearly 100% cannabidiol. EPIDIOLEX is manufactured with the highest standards of consistency, so the formulation is the same with every prescription.” In summary, Epidiolex is almost pure CBD with trace amounts of other phytocannabinoids.  Sativex® (delta-9-tetrahydrocannibinol and cannabidiol in the EU) (nabiximols in the USA), meanwhile, is described as “delta-9-tetrahydrocannibinol (THC) and cannabidiol (CBD) in a 1:1 ratio as well as specific minor cannabinoids and other non-cannabinoid components.” The naming convention of Epidiolex which refers to cannabidiol and CBD in the parentheses are very important to the drug vs. supplement discussion that is ongoing, which is largely focused on the CBD nomenclature.

In order to make room in the regulations for the GW Pharmaceuticals cannabis-derived drugs the controlled substances list language had to be adjusted to include them. This was accomplished as follows. The list moved “Approved Cannabidiol Drugs” to Schedule V with the following vitally important note under Other Names, “A drug product in finished dosage formulation that has been approved by the U.S. Food and Drug Administration that contains Cannabidiol derived from cannabis and no more than 0.1 percent (w/w) residual tetrahydrocannabinols.”

Full Spectrum Hemp Oil and the Difference Between Industrial Hemp Oil and Cannabis-Derived Drugs

Full spectrum hemp oil is another key term. Full spectrum hemp oil should refer to an oil that contains a natural spectrum of phytocannabinoids that are present in the cannabis plant used for extraction. It would be expected to contain a mixture of D9-THC, CBD, and other phytocannabinoids in whatever ratio is present in that particular cannabis plant.

Neither of the GW Pharmaceuticals drugs, Epidiolex or Sativex, is cannabis resin or oil in its natural full spectrum form. Both have been highly processed for a specific and consistent amount of CBD, D9-THC in the case of Sativex, or other components as outlined and are prescribed for use according to defined dosages. This is important when one returns to the distinction as to whether CBD should be considered a drug or a dietary supplement.

An Argument for How Industrial Hemp Oil Qualifies as a Legal Dietary Supplement Ingredient

The argument rages as to whether industrial hemp derived oil should qualify as a legal dietary supplement ingredient. In order to understand the argument one must understand the definition of a dietary supplement ingredient in the U.S. as defined in the Dietary Supplement Health and Education Act (DSHEA) of 1994; important excerpts are below.

(ff) The term “dietary supplement –
(1) means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:
(A) a vitamin;
(B) a mineral;
(C) an herb or other botanical;
(D) an amino acid;
(E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or
(F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E);…

NEW DIETARY INGREDIENTS SEC. 413. (a) IN GENERAL. – A dietary supplement which contains a new dietary ingredient shall be deemed adulterated under section 402(f) unless it meets one of the following requirements:

(1) The dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.
(2) There is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides the Secretary with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.

Industrial hemp derived oil certainly seems to qualify as a dietary supplement based on this language. Industrial hemp oil is an extract of the cannabis plant. Some researchers suggest the oil could be used to supplement the diet and influence the endocannabinoid system present in the human body. Cannabis resin or oil has been in the food supply prior to 1994 in a form not chemically altered as it has been used historically for centuries as an edible in a variety of cultural practices. There is a great deal of literature on the historical use of cannabis with one notation reading, “Smoking did not become common in the Old World until after the introduction of tobacco, so up until the 1500s hashish in the Muslim world was consumed as an edible.” The chemicals in the cannabis plant remain the same today.

Resolving the Question as to Whether CBD is a Drug or Supplement

The approval of the GW Pharmaceuticals cannabis-derived drugs has complicated the situation as the terms ‘cannabidiol’ and ‘CBD’ are now associated with the naming convention of the drug Epidiolex. Meanwhile, the dietary supplement industry has predominantly elected to market industrial hemp-derived oil products as ‘CBD products.’ This is why confusion has grown over categorization of CBD as it is now marketed as both a drug and a supplement.

The actual material is very different. The drugs are highly standardized phytocannabinoids produced to specific purity and/or ratio specifications. The DEA controlled substances list language dated October 1, 2018 defines “Approved Cannabidiol Drugs” as “a drug product in finished dosage formulation that has been approved by the U.S. Food and Drug Administration that contains Cannabidiol derived from cannabis and no more than 0.1 percent (w/w) residual tetrahydrocannabinols.” Industrial hemp oil is prepared in unspecified, non-specific ratios and is expected to be lower in CBD purity and content with higher amounts of other phytocannabinoids than Epidiolex. So, industrial hemp oil does not seem to comport with the definition of a cannabidiol drug used by the DEA.

Even though both are made with phytocannabinoids a distinction should be made between the specific ratios of phytocannabinoids used in the cannabis-derived drugs and the non-specific industrial hemp oil that has scientific merit to be legally categorized as a dietary supplement ingredient under the current DSHEA language. The ideal terminology to consider for dietary supplement ingredients derived from cannabis should include: ‘industrial hemp oil,’ ‘phytocannabinoids from industrial hemp,’ and ‘full spectrum industrial hemp oil.’

Cannabinoid profile testing can be used to distinguish between industrial hemp oil dietary supplement ingredients and the specific drugs Epidiolex and Sativex. So there is a scientific solution but what about a terminology solution? Could the term ‘CBD’ be isolated to refer to Epidiolex while the dietary supplement industry uses the language suggested above to differentiate the two categories? Yes, but ‘CBD’ has become so engrained already within the terminology of the dietary supplement industry changing its use now would prove challenging.

Whether the drug or dietary supplement industry gets to lay claim to the term ‘CBD’ and how that relates to marketing seems to be the crux of the remaining argument, as well as the controlled substances list language. The existing regulations as written should be able to distinguish the two categories as outlined herein although this remains to be clarified. Meanwhile, the industrial hemp oil industry continues to expand and grow despite the regulatory quandary on legality and categorization.

Quality Control Concerns and Introduction of the BSCG Certified Hemp Program

BSCG Certified HempWith the growth of the category has come expanded quality control concerns. Do industrial hemp oil products adhere to good manufacturing practices (GMP)? Are they properly tested for contaminants like pesticides, heavy metals or solvents? Do the products really test below the legal 0.3 percent D9-THC limit outlined? Are any dangerous synthetic cannabimimetics being substituted for natural phytocannabinoids? Could these products make an athlete fail a drug test? All of these are good questions.

At BSCG, we don’t just aim to outline problems; we like to offer solutions! In that effort, BSCG is pleased to introduce our new third-party certification program BSCG Certified Hemp™. We are excited to provide a new level of transparency and quality control to the industrial hemp product industry and help address important consumer concerns in the process.
– Oliver Catlin, BSCG President

BSCG The Gold Standard in Dietary Supplement Certification

Transparency in Third Party Certification for Banned Substances in Sport

May 31, 2018

BSCG – Committed to transparency in third party certification for banned substances in sport

BSCG The Gold Standard in Dietary Supplement CertificationAt BSCG, we believe transparency in third party certification for banned substances in sport is crucial. Not only does transparency allow an understanding of the underlying protection offered, it fosters trust in the testing process.

To be transparent, a certification provider should clearly describe the fundamental aspects of certification; the drugs included in the testing menu, detection or reporting levels or other thresholds used; and a list of batch numbers that have been certified. BSCG’s commitment to transparency and open communication, along with our independence and scientific expertise in the field of sports doping control, set us apart from our competitors.

BSCG has set the highest standard with respect to transparency in third-party certification for banned substances in sport. Look for clarity from us on all of our program elements at every step.

Testing Menu

The BSCG Certified Drug Free® testing menu is clearly defined on our website. BSCG is currently the only leading third-party certification provider to have a page on its site that provides the details on its testing menu. The BSCG Certified Drug Free® industry leading testing menu protects against more than 274 drugs banned in sport and an additional 211 prescription, over-the-counter, or illicit drugs not banned in sport– which no other provider covers.

Detection and Reporting Levels Used

BSCG offers a clear explanation of the detection and reporting levels used to certify products. If we find a compound banned in sport, we report it and do not certify the product (except in rare instances as when a compound may be naturally present at insignificant trace levels in an ingredient). BSCG does not believe in, nor do we employ, maximum allowable level per serving thresholds for any of the performance-enhancing drugs in our testing menu. BSCG detection levels are in the 10-100 parts per billion (ppb) range for most compounds in most products, with a few drugs in the 100-500 ppb range; detection levels can vary by matrix and may be lower or higher in some products.

Listing of Certified Batches

BSCG provides each individual finished product batch number that has been certified on our online database and certified product page listings. Most of our clients certify every finished batch, although we also offer a monthly testing option. We believe in clarity when it comes to the scope and scale of what has been tested. We do not have any hidden testing schemes or fine print to worry about, and we do not use general undefined terms in our database listings.

Thankfully, the nutrition industry as a whole is moving toward greater transparency, a development we have long advocated. BSCG is proud to be leading the charge in our corner of the industry for full disclosure of fundamental elements of third-party certification for banned substances in sport. We are honest and open with what we certify and how we do it. Trust, we believe, demands transparency.

 

Noopept could be the next big banned substance in sport after meldonium

Noopept could be the next big banned substance in sport after Meldonium

August 8, 2016

Noopept could be the next Meldonium

Written by Oliver Catlin, BSCG President

The question many of us continually ask, “What might be the next clandestine doping agent in sports?” might have a new answer: noopept. Popular in dietary supplements, noopept could be the next big banned substance in sport after meldonium.

As we watch the 2016 Rio Olympic Games with the Russian doping scandal looming in the rearview mirror the notion that noopept could be the next big banned substance in sport after meldonium is interesting on its own. However, when one considers that both substances appear to be sold as medication in Russia, and that many of the meldonium findings early this year involved Russian athletes, the intrigue gets deeper. Because noopept is prevalent in the supplement marketplace around the world, if it is the next clandestine doping agent the potential issue would expand well beyond Russia.

A comparison between the substance noopept and meldonium supports our theory. Meldonium, which is suggested to improve blood flow, is approved for use as anti-ischemia medication in Eastern Europe and Russia. It is usually used to treat heart disease. Although clearly popular with athletes, based on the hundreds of adverse analytical findings for the drug in early 2016, meldonium is not commonly found as a dietary supplement, at least not yet.

Meanwhile, noopept, is patented by JSC LEKKO Pharmaceuticals, a Russian pharmaceutical company, in both the U.S. and Russia. It is commonly sold as a dietary supplement in the nootropic category around the world, but appears to be sold as a medication in Russia and Eastern Europe. Noopept is being studied for its potential to alleviate Alzheimer’s symptoms and treat other brain disorders. It is not an approved drug in the U.S.

Noopept does not appear to be a controlled substance in the U.S. or other countries, or at least that is what some nootropic sites claim. That does not mean, however, it would be legal to sell as a supplement. It would likely qualify as an unapproved drug according to the U.S. FDA, or other international equivalents. As such, it may be OK to sell for research purposes, but not as a supplement marketed for human consumption. Given that noopept was patented in 1996, was not in the food supply prior to 1994, and is synthetic, it does not appear to qualify as a legal dietary supplement ingredient in the U.S., according to DSHEA (the Dietary Supplement Health and Education Act of 1994).

Despite noopept being a dubious, if not illegal, supplement ingredient, it is commonly found packaged as a supplement and is available online at a wide range of distributors including Amazon.com and Jet.com. Based on its prevalence in dietary supplements and on message boards, it seems it has become quite popular. With discussion on ‘The Worlds Most Trusted Anabolic Website,’ as far back as 2007, it appears folks that track performance-enhancing compounds have known about it for a number of years.

In fact, noopept has become so popular that even Reddit, who thankfully realizes the concern, has a note on noopept in ‘New Rules in Regards to Illegal/Dangerous Compounds.’ The note describes that, “synthetic drugs (not DSHEA compliant) that have too little information on them to assess toxicity (Ex. Noopept or PRL-8-53)…, are in the grey area.”

So, what does noopept do and why might it be prohibited in sport?

As mentioned, noopept is typically marketed as a nootropic, or in simple terms a brain stimulant. Nootropics are different than central nervous system stimulants, but are suggested to have some psychostimulatory effects. Noopept’s effect is often compared to piracetam, which the Global DRO does not consider prohibited in sport, and phenylpiracetam (carphedon, fonturacetam), which is prohibited in sport. An excerpt from Racetam.org compares phenylpiracetam to noopept as follows:

“Even though phenylpiracetam is considered 60 times more potent than piracetam, noopept is considered to be around 1000 times more effective. This is because it often works through the acetycholinergic system in ways that are different from the other racetams. Structurally speaking, noopept is not the same family as racetams, but it is similar and definitely acts in similar ways.”

So, noopept could perhaps be interpreted as prohibited in sport already based on the catch-all language used in the WADA (World Anti-Doping Agency) Prohibited List. Meldonium needed to be added to the list by name, where it now appears as a metabolic modulator. This is an important distinction, as there is precedent for related substances being considered banned in sport and resulting in positive drug tests even before they are on the WADA Prohibited List. That was the case with DMAA when the first positive was called in 2008, and recently occurred again with higenamine early in 2016.

The stimulant category includes fonturacetam [4-phenylpiracetam (carphedon)] as a non-specified stimulant. The catch-all language at the end of the category prohibits, “other substances with a similar chemical structure or similar biological effect(s).” Noopept, shown at left, may qualify as it is described as having a similar biological effect and seems to have a similar structure as phenylpiracetam. Interestingly, the phenyl group in the upper left corner is also shared by phenethylamine, which was added to the WADA Prohibited List in 2015.

We note that if fonturacetam is prohibited in sport then piracetam could also qualify under catch-all language in our view, but it does not according to the Global DRO. So, interpretation does not seem clear as to whether something that appears to have a similar chemical structure and structure to fonturacetam is prohibited in sport. Would other more potent racetams like aniracetam be interpreted to be prohibited? We believe they would be, but then noopept could be as well.

You can see why noopept could be the next big banned substance in sport after meldonium. It is widely available making it likely to be used by athletes. It could have the potential to enhance sports performance as it is described as having similar biological effects as phenylpiracetam, which is already banned in sport. It would likely satisfy the first and third conditions for a drug to be considered for addition to the WADA Prohibited List.

1 – Potential to enhance or enhances sports performance
2 – An actual or potential health risk to the athlete
3 – Use violates the spirit of sport (outlined in the Code)

With the 2016 Rio Olympic Games in progress we find ourselves wondering what drugs athletes might be using. Noopept is hiding in plain sight and could be exposed soon as the next clandestine doping agent. Whether that holds true depends on if, or when, WADA interprets the substance to be prohibited. That could happen at any time if they see the situation as we do.

n-methyltyramine supplements are prohibited in sport

August 6, 2016

N-methyltyramine supplements are prohibited in sport but the same substance is acceptable when naturally present in beer

Beer Contains a Prohibited Substance in SportIn a recent blog post, we marveled at the seemingly absurd notion that beer might be banned in sport based on interpretation that a prohibited substance, N-methyltyramine (NMT), is present at around three milligrams per pint. After a pint or two, we thought more clarity was necessary for our fellow imbibers. When present naturally in beer NMT would be acceptable, while n-methyltyramine supplements are prohibited in sport. This presents an interesting dilemma to students of anti-doping regulations and lists.

How is it that that one substance can be both legal, and naturally present in beer, but also be a prohibited substance in sport? Who exactly is responsible for this absurdity? Well, you can blame it on the resurgence of n-methyltyramine as a stimulant and/or weight loss ingredient in dietary supplements and the addition of phenethylamine and its derivatives to the WADA Prohibited List in 2015.

The resurgence of NMT in the supplement arena came as far back as 2011, but the phenomenon has surged again recently as companies have looked for replacements for dubious ingredients like DMAA (dimethylamylamine, or methylhexaneamine). DMAA was often sold in disguise as natural geranium oil extract, but in reality what was on the market was the synthetic chemical DMAA. DMAA became perhaps the most popular stimulant pre-workout ingredient ever but has since run into regulatory action after adverse events and determination by the FDA, and international equivalents, that it is an illegal supplement ingredient. DMAA has also become the most common stimulant reported as an adverse analytical finding in the WADA system.

N-methyltyramine was a logical substance for the supplement makers to turn to since it is naturally present in barley as we pointed out previously, and citrus aurantium. Citrus aurantium also contains other stimulants like synephrine and octopamine (the later banned in all sport, the former banned in the NCAA). Citrus aurantium and synephrine have been popular stimulant and weight loss supplement ingredients for many years. So, the theory is that n-methyltyramine, being a phenethylamine derivative, and naturally present, would be a perfect replacement ingredient.

As a phenethylamine derivative, n-methyltyramine qualifies as a prohibited stimulant based on the WADA Prohibited List language in force today. While it qualifies as a stimulant, it may not be all that effective as a stimulant or weight loss agent. Nonetheless, this has not stopped the supplement community from peddling it as a weight loss ingredient still today. Even sites that promote NMT note the dubious efficacy of this relatively unstudied compound, as the excerpt below demonstrates.

“This compound is often included in weight loss formulations, despite evidence pointing to the fact that N-methyltyramine has been shown to inhibit fat breakdown and stimulate pancreatic hormones like anabolic insulin, and gastrin, which stimulate appetite (5). That said, the stimulant effect of this ingredient is likely to suppress appetite, and it is probable that N-methyltyramine will work for some people well but perhaps not for others. Additionally, the effect of N-methyltyramine as a stimulant has been called into question, because, like tyramine, it has low lipid solubility, therefore it is unlikely to cross the blood-brain barrier.”

The usual amount of NMT used as an active ingredient in supplements is around 200 milligrams. That compares to around 3 milligrams of NMT per pint of beer. So, you would need to drink around 70 beers to ingest the same amount of NMT you would get in a supplement. Stimulants generally clear the body fairly quickly. So, even if you had one beer a day or two before competition that would be unlikely to cause an NMT adverse analytical finding, while n-methyltyramine supplements are prohibited in sport.

Perhaps interpreting NMT as prohibited in sport will dissuade supplement manufacturers from making supplements with n-methyltyramine as an active ingredient. We rather doubt it, since often when something is banned in sport it encourages the proliferation of dietary supplements that contain the banned substance as an ingredient. This happened with Cobalt, SARMs, DMAA and others. Nonetheless, interpreting NMT as prohibited at least discourages athletes from using NMT supplements. We certainly support the prohibition of dubious stimulant and weight loss substances.

At the end of the day, n-methyltyramine supplements are prohibited in sport while the same substance is acceptable in beer. Many natural compounds share a similar predicament. They may be banned if synthesized and used as an active ingredient but acceptable in the natural form. We should be able to defend legitimate natural products, and beer, while also combating problematic synthetic compounds masquerading as legal supplement ingredients like DMAA. The problem is that determining whether a compound is natural, legal, or prohibited in sport can be a complex challenge when considering substances like N-methyltyramine.

Higenamine, a natural product banned in sport

Higenamine, a Natural Product Banned in Sport

August 2, 2016

Dietary Supplements and Banned Substances – A Case Study on Higenamine, a Natural Product Banned in Sport

Athletes should be allowed to focus completely on the sport at hand but instead they are frequently plagued with concerns over whether a dietary supplement, natural product, functional food, or medication they are taking will cause a positive drug test and derail their athletic career. The exercise of determining whether or not something is banned in sport can be extremely difficult. A perfect example of the challenge comes in the form of Higenamine, a natural product banned in sport.

Why is Higenamine a natural product banned in sport? This happens because of the philosophy and approach to creating banned substance lists and the use of catch-all language to cover substances that are related or similar to those on the list but are not named. Amazingly, in some environments like Olympic sport, Higenamine is interpreted as prohibited but does not actually appear on the list. So an athlete has to know how to interpret that such a compound is prohibited.

is a naturally present compound found in a number of different plant species including certain aconitum ( the napellus variety is shown at left), bamboo, poppy, lotus, and magnolia tree varieties. If derived from a natural source, it is a legal dietary supplement ingredient in the US, UK, EU and Canada. A , or biological effect. Since beta-2 agonists are banned by some sporting groups, Higenamine became prohibited based on the interpretation of the list language.

In the case of the various versions of catch-all language are used in the different prohibited categories. Some categories say that, ‘substances with a similar chemical structure or similar biological effect(s)’ are banned. Other categories use ‘including, but not limited to’ language to cover compounds that are not listed. Overall, WADA lists approximately 280 drugs on the Prohibited List but many more could be interpreted to be prohibited based on catch-all language. The extent of the interpretation is not known and is at WADA discretion.

Germane to Higenamine is the language in section S3 – Beta-2 Agonists of the WADA Prohibited List. It says, ‘All beta-2 agonists, including all optical isomers, e.g. d- and l- where relevant, are prohibited.’ This is very broad language that seems to include Higenamine by interpretation since at least one study shows that Higenamine has some beta-2 agonist activity.

Meanwhile, the NCAA takes a similar approach to prohibiting drugs by category, but they include a much smaller list of examples. The list includes a note that, ‘Any substance that is chemically related to the class, even if it is not listed as an example, is also banned.’ They go on to note, ‘There is NO complete list of banned substances,’ and ‘It is your responsibility to check with the appropriate or designated athletics staff before using any substance.’

In the NCAA they actually include Higenamine, and its alternate nomenclature Norcoclaurine, as examples of beta-2 agonists along with traditional pharmaceutical beta-2 agonists like Salbutamol. Under the NCAA list language anything that is chemically related to Higenamine could also be considered banned, even if the related substances have not shown activity as a beta-2 agonist. There are many . So, by interpretation, Higenamine and a variety of other compounds could potentially be banned in the NCAA.

If you look at the situation in professional sport taking MLB as an example, the situation with Higenamine gets even more interesting. A review of the unveils that MLB does not appear to prohibit beta-2 agonists. Beta-2 agonists are not mentioned as a prohibited category. MLB does stipulate that ‘the following is a non-exhaustive list of substances that shall be considered prohibited,’ but without mentioning beta-2 agonists as a category it is hard to imagine these would be interpreted to be banned. No beta-2 agonists are included in the MLB list as examples.

In golf, soon to make its return to the Olympics in Rio after 112 years of absence, the consideration of whether Higenamine is banned is of particular interest. It turns out that both the PGA and LPGA follow the MLB example and do not prohibit the category of beta-2 agonists. The lists do have catch-all language like others, but with the category not being mentioned the catch-all language is not likely to cover beta-2 agonists. So, it appears that beta-2 agonists are not prohibited in professional golf.

Now imagine you are a golfer progressing from the NCAA to the PGA or LPGA and now have the opportunity to play in the Olympics and are subject to WADA rules. In the NCAA, Higenamine is explicitly prohibited, in professional golf it appears not to be prohibited, while at the Olympics Higenamine appears to be prohibited by interpretation. Got that straight?

Not to confuse things further, but we should point out that in our view Higenamine would actually be more appropriately prohibited as a stimulant not a beta-2 agonist. Higenamine typically appears in pre-workout stimulant supplements as a replacement for previously popular ingredients like DMAA, or methylhexaneamine, which was first banned in sport in 2009 classified as a stimulant. If someone were to consider Higenamine as a stimulant then the compound could be considered banned in professional sports like MLB, or golf under the catch-all language for stimulants. As you can see it all comes down to interpretation.

The question of whether Higenamine was prohibited by interpretation was challenged recently when a for it prior to the 2016 Europa League Final. He was originally sanctioned but the sanction was lifted after the player successfully argued that there was an absence of negligence because Higenamine was not on the list of banned substances despite the category being banned. Whether this argument would prove to be a successful defense in other situations where the WADA list language is relevant is not known. WADA is reviewing the case.

As you can see, whether or not Higenamine is banned in sport is quite an interesting question. In WADA, it is not listed as a prohibited substance but is interpreted to be a beta-2 agonist and has led to positive drug tests. In the NCAA, Higenamine appears as an example of a prohibited beta-2 agonist, even though it is technically not chemically related to other pharmaceutical beta-2 agonists like salbutamol. Finally, in MLB, PGA, or the LPGA, Higenamine does not appear to be prohibited unless it is interpreted to be a stimulant as we would argue it could be.

Higenamine, a natural product banned in sport, is a good example of the challenges athletes and others face when trying to interpret whether natural products or supplement ingredients are prohibited. Do not try this at home!

We encourage athletes not to make such interpretations without the assistance of a qualified expert. We are happy to review products for athletes or their personnel anytime. We also recommend that athletes consider products that have been certified to be free of banned substances in sport by a third-party. We proudly offer certification under the BSCG banner.

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Beer Contains a Prohibited Substance in Sport, N-methyltyramine

July 16, 2016

N-methyltyramine, prevalent in beer, is interpreted as prohibited in sport based on the World Anti-Doping Agency Prohibited List.

Beer Contains a Prohibited Substance in Sport

We have made a frothy discovery. As it turns out, beer contains a prohibited substance in sport. This was a surprising realization to us as we are sure it is for you, but it appears to be true, at least by interpretation. Seriously? It’s ludicrous to consider that beer contains a prohibited substance in sport. Here are the facts behind this intoxicating notion.

In 2015, the World Anti-Doping Agency (WADA) added new prohibited substances to the WADA Prohibited List, as they do each year. “Phenethylamine and its derivatives” were added to the list with little fanfare or attention, which is likely because the implications of that addition had not been fully considered. The significance, in fact, is vast and potentially affects hundreds of natural products and plant extracts. The scope of adding this language can be understood after reading one publication alone, “Phenethylamine and related compounds in plants”, which was published in Phytochemisrry in 1977.

The paper characterizes approximately 200 plant species that naturally contain phenethylamine or its derivatives. Phenethylamine derivatives are a very broad category of substances. They include psychoactive substances or controlled substances like; amphetamine, cathine, ephedrine, methamphetamine, octopamine, and pseudoephedrine, all of which are specifically mentioned on the WADA Prohibited List by name. We are fully supportive of these dangerous substances, and any closely related derivatives, being regulated as controlled substances and banned in sport.

Some phenethylamine derivatives, however, are naturally occurring in plants and animals like tyramine (the scientific name of which is 4-hydroxyphenethylamine), or dopamine (the scientific name of which is 3,4-dihydroxyphenethylamine), or adrenaline. Tyramine is present in significant quantities in chocolate, avocados, plums, pork and cheese. Are these naturally occurring phenethylamine derivatives really considered banned in sport by interpretation? Do they really qualify as controlled substances, as tyramine has been deemed to be under Schedule 1.c. #66 in the Sunshine State of Florida? Well that logic just may be tested with beer.

Barley, it turns out, is one of the plants that naturally contains a derivative of phenethylamine. Specifically, it contains a compound called N-methyltyramine (NMT), also known as 4-hydroxy-N-methylphenethylamine. A casual review of NMT’s Wikipedia listing reveals some startling facts that have been apparent from publications as far back as the 1950s and 1960s:

“NMT was isolated as a natural product for the first time, from germinating barley roots, by Kirkwood and Marion in 1950. These chemists found that 600 g of barley, after germination and 10-day growth, yielded 168 mg of N-methyltyramine.[5] Since barley, via its conversion to malt, is used extensively in the production of beer, beer and malt have been examined by several groups of investigators for the presence of NMT. Citing a 1965 study by McFarlane,[6] Poocharoen reported that beer contained ~ 5–8 mg/L of NMT.[7]

We did the math for you: A friendly neighborhood pint of beer contains between 2.3 – 3.8 mg/pint of N-methyltyramine. It should be noted that milligram quantities are relatively high amounts, not trace levels. Medications and dietary supplement ingredients are commonly found in milligram quantities. Ingesting milligram quantities of a stimulant banned in sport would be highly likely to result in an athlete testing positive.

Beer qualifies as banned on WADA Prohibited ListIf you think this is only a theory we brewed up, that’s not the case, I’m afraid. We consulted the Global Drug Reference Online, or Global DRO. The Global DRO is a ‘partnership between UK Anti-Doping (UKAD), the Canadian Centre for Ethics in Sport (CCES) and the United States Anti-Doping Agency (USADA). The Japan Anti-Doping Agency (JADA) and the Australian Sports Anti-Doping Authority (ASADA) are official Global DRO licensees.’ The Global DRO ‘provides athletes and support personnel with information about the prohibited status of specific substances under the rules of sport based on the current World Anti-Doping Agency (WADA) Prohibited List.’ For those unfamiliar with it, the Global DRO is a great site for Olympic athletes to explore whether medications or other substances are banned in sport. Supplement ingredients are not often considered, but the site is nonetheless a good resource.

We wanted to see if tyramine was considered prohibited, but it did not come up in Global DRO search results so we could not explore whether it would be interpreted as banned. What did come up was N-methyltyramine, which was indicated as Prohibited under the S6 – Stimulant category. This makes NMT prohibited in competition but not out of competition. This prompted us to explore the possible natural presence of NMT, which led us to the conclusion that beer contains a prohibited substance in sport. This is not good news to even casual beer-drinking athletes. (Interestingly, dopamine, also appears in the Global DRO database but it is not interpreted to be prohibited despite being a phenethylamine derivative.)

Surely there must be some explanation. If NMT is interpreted as prohibited there must not be enough to cause a positive drug test, right? Well, let’s consider the details. NMT would be considered a specified stimulant in the WADA system under category S6.b, which means urine thresholds would apply to avoid positives from environmental presence. However, as we noted earlier, one ingests MILLIGRAM quantities of N-methyltyramine in just one pint of beer.

Hopefully athletes are not drinking a lot of beer while in competition, but could a beer on a night off a cycling race, or three beers one week before a swim meet potentially impact a drug test? Perhaps there are urine excretion studies that can answer more definitively how much beer you would have to drink, and when, in order to test positive for N-methyltyramine. We have not fully explored this. Ultimately, we believe the answer to this whole dilemma is that N-methytyramine falls into a strange category of substance. A compound banned by interpretation but not in practice, at least not in all forms.

By this we mean a substance that could be interpreted to be banned based on catch-all language in the WADA Prohibited List like ‘including but not limited to,’ or ‘substances with a similar chemical structure or similar biological effect(s).’  Catch-all language appears in every category of the WADA Prohibited List except for S4.5 – Metabolic Modulators (where meldonium appears), S7. – Narcotics, and S8 -Cannabinoids (all categories we suggest could be worthy of catch-all language).

Debating this theory may seem like an amusing matter, but athletes’ careers hang on these very types of questions. Our business of dietary supplement certification at BSCG also hinges on the interpretation of whether supplement ingredients, natural products, or functional foods contain substances banned in sport. When one considers that hundreds of plants species including things like barley, spinach, or aloe vera contain phenethylamine or its derivatives that may be banned in sport, the concern is greatly magnified.

If the Global DRO interprets that N-methyltyramine, which is present in beer in milligram quantities, is prohibited, exactly where does the scope of this start or stop? That remains a good question, and one that we hope is not answered by first having an athlete fall victim to testing positive from the natural presence of phenethylamine or its derivatives. It would be a true shame if that were to happen simply from enjoying a pint.

So, what is the solution? We suggest perhaps refining the nomenclature to list ‘Synthetic psychoactive phenethylamine derivatives.’ This option would alleviate the interpreted prohibition of benign natural phenethylamine derivatives like tyramine while still covering substances like the N-alpha-diethylphenethylamine (N-a-DEPEA) derivative identified in the Craze pre-workout supplement, which is what prompted the prohibition of phenethylamine derivatives in the first place.

We fully support combating dangerous phenethylamine derivatives like N-a-DEPEA–but not beer. We have to do a better job of clarification and interpretation of the prohibited substance list language on behalf of the athletes that rely on anti-doping rules to protect, not inadvertently derail, their careers and passion for competing. The Olympic Motto is Citius, Altius, Fortius. Let’s add Magis.

Although beer contains a prohibited substance in sport, at least by interpretation, it does not appear that drinking beer will cause a positive drug test in practice. Cheers to that!

Banned Substances in Supplements

Athletes, Are you Doping on Accident with Hidden Banned Substances in Supplements?

June 14, 2016

Hidden banned substances in supplements can keep athletes out of the Olympic Games: Jessica Hardy and Pavle Jovanovich cases serve as a warning

A number of athletes have tested positive from the hidden presence of banned substances in supplements and have lost the opportunity to compete at the Olympic Games. This summer on the road to Rio, Olympic athletes of every stripe would be wise to recall the case of American swimmer Jessica Hardy and others like American bobsledder Pavle Jovanovich who have fallen victim to supplement contamination. Third-party dietary supplement certification, like our BSCG Certified Drug Free® program, is a way for athletes to mitigate the risk of testing positive from banned substances in supplements.

2008 Beijing Olympic Games Swimming - Photo by Oliver Catlin

2008 Beijing Olympic Games Swimming – Photo by Oliver Catlin

Eight years ago, a twenty-one-year-old Hardy was pulled from the 2008 Summer Olympic team heading to Beijing after testing positive for the banned anabolic agent clenbuterol at the Olympic Trials. Instead of getting to swim the 100-meter breaststroke, 50-meter freestyle, and 4×100-meter freestyle relay for which she had qualified, she was smacked with a two-year ban. Not only that, her career was now marred with a doping violation, casting a shadow over all of her athletic achievements.

clenbuterolHardy maintained her innocence, saying she had never before heard of clenbuterol. Some in her entourage, including a coach, pointed to the possibility of banned substances in supplements she had been consuming as a potential culprit for the positive drug test.

Under WADA (World Anti-Doping Agency), USADA (U.S. Anti-Doping Agency) and IOC (International Olympic Committee) rules, however, ignorance about a substance being banned or lack of awareness of how a banned substance entered the body, referred to as ‘inadvertent use,’ are not valid excuses. Athletes are responsible for any banned substance they ingest, regardless of the means, which is known as ‘strict liability.’

At the time, the USOC (United States Olympic Committee) Athlete Ombudsman suggested to Hardy and her team that she consider having her supplements tested by renowned anti-doping guru Dr. Don Catlin, BSCG’s Chief Science Officer. After rigorous testing, Dr. Catlin and his team at the nonprofit/NGO Anti-Doping Research did indeed find trace amounts of clenbuterol in a legally sold supplement Hardy had been taking, Arginine Extreme, a sports-nutrition drink produced by AdvoCare. AdvoCare’s own testing of the product had come up clear of any banned substances.

At an American Arbitration Association panel in 2009, Dr. Catlin testified on Hardy’s behalf. He explained his test results and noted that AdvoCare might not even have been aware of the drug’s presence, as supplements have a supply line of ingredients and these ingredients can be contaminated. Indeed, banned substances often infiltrate products at the raw material stage, and in many circumstances the supplement brand has no knowledge of the issue.

In consideration of Dr. Catlin’s review and the inadvertent use of clenbuterol by Hardy, the panel halved Hardy’s ban to a year. The next year, following an appeal by WADA, the Court of Arbitration for Sport upheld the decision. Unfortunately for Ms. Hardy, she had spent much time and effort to reduce her sanction and repair her reputation.

Though Hardy returned to the sport she loves, went on to break world records in the breaststroke, and won relay medals, including gold, at the 2012 Summer Olympics in London, there will always be a gap in her career as well as the one Olympic Games she can never get back.

“I hear about (those medals) all the time,” she told the Wall Street Journal in 2012, of the races won by other swimmers at Beijing. “Hardy never used to be an angry person,” the same article stated. “But after the disqualification fiasco, her coach, Dave Salo of the Trojan Swim Club in Los Angeles, says she became prone to ‘act out and storm off’ after occasional bad swims.” Hardy has sought therapy in order to manage the anger and negative thoughts fostered by her unfortunate circumstances.

Hardy is not the only Olympic athlete to have been affected by banned substances in supplements. Just prior to the 2002 Salt Lake Olympic Games American bobsledder Pavle Jovanovich tested positive for the anabolic steroid 19-norandrostenedione. The result had a serious effect on him. “‘It was just a nightmare for me,” he said in an interview later, adding that he felt “completely detached” from family and friends and that he “did battle alcohol.” He blamed the finding on a dietary supplement called Nitro-Tech and ultimately received a settlement from Century Foods. (This short piece, in the San Diego Union-Tribune, summarizes the cases of seven other athletes who also filed suits against supplement companies in relation to positive drug tests.)

These examples serve as a reminder to all athletes and Olympians to be aware of what they are putting into their bodies, at all times. Inadvertent presence of banned substances in supplements can result in serious penalties. Recent studies have revealed the majority of elite athletes consume dietary supplements, making supplement safety and risk management strategies for these athletes vital.

BSCG - Do you really know what is in your supplements?There are simple ways for athletes to mitigate the risks, as we describe on the Supplement Information for Athletes page of our website. One of the most effective methods is to only use supplements that have been certified by a third-party to be free of banned substances, like those that participate in our BSCG Certified Drug Free® supplement certification program (click here for a third-party dietary supplement certification program comparison). After more than 12 years of offering certification, no supplement BSCG has certified has ever led to a positive drug test.

Athletes, don’t let banned substances in supplements keep you out of the Olympics or tar your achievements there. To protect yourselves, your careers and your sports, make sure you consider taking only dietary supplements and natural products that have been certified by a trusted third-party provider to be free of banned substances.

Stay Clean and Win Clean! Support Clean Sport!

The Olympic Charter

The Russian Doping Scandal and the International Olympic Charter Against Doping in Sport

June 1, 2016

Backstory: The Russian Doping Scandal, the Olympics, and the International Olympic Charter Against Doping in Sport

The Olympic Charter Sadly, an ongoing Russian doping scandal has challenged the central tenets of the International Olympic Charter Against Doping in Sport. The debate rages at the highest levels of sport about whether Russian athletes should be allowed to participate in this summer’s Olympic Games in Rio. This follows an investigation overseen by former WADA president Dick Pound last fall finding Russia’s track and field program was corrupt and riddled with systematic doping. Earlier this year, a large number of Russian athletes tested positive for the banned substance meldonium. And two weeks ago, the head of drug testing for the 2014 Sochi Winter Olympics, Professor Grigory Rodchenkov, alleged a scheme in which he, at the behest of the Russian government, oversaw doping of Russian Olympic athletes and result tampering.

Back in 1988, at an international sports anti-doping conference in Ottawa, Canada, 85 delegates of sport, doping control, and government representing 27 nations and the IOC (International Olympic Committee) met to refine and approve the first International Olympic Charter Against Doping in Sport. The guide was meant as an official code of conduct for sporting organizations, countries, and athletes participating in the Olympics.

Don Catlin, M.D.BSCG’s Chief Science Officer, Dr. Don Catlin, a longtime IOC Medical Commission member who founded and directed the UCLA Olympic Analytical Laboratory prior to the Los Angeles 1984 Summer Olympics, worked with a small group of colleagues to first propose the idea of the charter and was a co-writer of the document. The need for a more definitive set of principles and rules had been building since an anti-doping declaration of athletes and coaches at Baden-Baden in 1981 and a call from the IOC’s Athletic Commission in 1985 for stronger doping controls and more severe sanctions.

The original charter, written in both English and French, was approved by the IOC and endorsed unanimously by all represented countries and related organizations. Meant as both a values statement and a practical guide, it contained a preamble outlining principles and seven sections covering such topics as banned drugs, sample testing, and guidelines for out-of-competition and short-notice testing.

The charter describes the importance of anti-doping rules to sport. Doping agents in sport, it states, are “both unhealthy and contrary to the ethics of sport,” so it is necessary to set rules with the intent to “protect the physical and spiritual health of athletes, the values of fair play and of competition, the integrity and unity of sport, and the rights of those who take part in it at whatever level.”

At the end of the charter’s preamble, the countries agree the “following elements are fundamental elements of a common anti-doping policy and strategy, and that they should be applied by governments and sports organizations, acting both individually and in co-operation” as well as “to implement those measures which are within their competence, and to encourage their partners to implement those which fall within their powers.”

The document acknowledged national anti-doping programs could vary from nation to nation depending on the particular government or sport structure, but that certain program elements were considered fundamental to any national anti-doping program. These essentials included a published national anti-doping policy, national coordination, an anti-doping experts advisory group, accredited laboratories, doping control via scientific testing, due-process mechanisms, and education programs.

Annex 6 related to the rights and responsibilities of sports organizations, athletes, and their entourage. The responsibilities of sports organizations were clearly stipulated: “To take all the appropriate steps to organize fair competitions and, in particular of this context, free from doping and to protect athletes and competitors who compete in a fair and equal manner and to exclude those who attempt to benefit from undue use of banned doping classes or methods.”

Since its 2013 report on the ‘Lack of Effectiveness of Testing Programs‘, WADA has been suggesting that a key challenge for the global anti-doping effort is getting stakeholders such as sporting organizations and governments to buy into the ideal of clean sport and has acknowledged that this hasn’t been achieved. The ongoing clamor surrounding the Russian doping scandal illustrates the point well, as it only takes one stakeholder such as Russia to go awry for the whole Olympic system to be thrown out of balance and the credibility of the Games to be undermined.

Whether Russian athletes will be allowed to participate in the upcoming Summer Games remains to be seen. But the letter and spirit of the International Olympic Charter Against Doping in Sport have been clear for 28 years. From the start, the Olympics’ official code of ethics was a useful tool in identifying whether a country was in violation of doping standards, and it remains so today.

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