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.
The 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.
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.
Follistatin 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.
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?
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.
It 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.
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
The 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.
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.
(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.
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 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
With 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