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

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

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

In 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 ingredien 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

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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