7 Potent Ingredients Every Supplement Nerd Should Know About
7 Potent Ingredients Every Supplement Nerd Should Know About
Is it or isn't it?

What am I talking about? Is it a dietary ingredient (and hence OK to use in a dietary SUPPLEMENT) or is it – maybe? – not really a dietary ingredient and this not OK having no business being sold under the rubric of DSHEA 1994 as a "dietary supplement?"

Disclaimer: I am not an attorney so this all is my layman's opinion here. Additionally, more or less, only the FDA or a federal court - and perhaps sometimes our Congress if they ever managed to send any bills to the POTUSA to actually sign - may definitively determine whether it "is" or it "isn't."  However, with that disclaimer out of the way here are my "top" reviews of ingredients currently being openly sold today as dietary ingredients found in dietary supplements that I receive questions about as to their status.

Ingredient #1 - Rauwolfia Serpentina: The "Fat Burner"

Rauwolfia serpentina, which is also known as Indian Snake Root, ostensibly contains a bunch of interesting indole alkaloids including rauwolscine (sometimes known as "alpha-yohimbine") which supplement producers like to use for the putative fat burning and peripheral stimulant effects via the alpha-2 receptor. It also likely contains reserpine, another indole alkaloid, unless it specifically says on the label that it does not.

Reserpine is absolutely a prescription drug in the USA.

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Bruce Kneller is the Chief Formulator for Giant Sports supplements.
I would argue there is no way this plant is ever going to be acceptable for use as a dietary ingredient. The herb itself is likely to be considered a drug. It was used to treat high blood pressure, and oddly schizophrenia, in humans. There is a ton of evidence from the 1940's and 1950's in peer reviewed publications to support this contention and I can find no evidence that it would be grandfathered in as pre-DSHEA 1994.

As an aside, which is not germane to the legality of the plant in the USA per se, is that very likely the addition of any rauwolfia species (e.g., Rauwolfia vomitora aka Poison Devil's Pepper) may cause an anti-CNS stimulant effect due to the actions of many of the indole alkaloids on the vesicular monoamine oxidase transporter at the neuronal cleft. In a nutshell – this stuff quite possibly will make most PEA-based compounds less effective as they will increase the metabolic deamination of most PEA-based compounds in the brain.

Yes, I am aware that yohimbine has some purported and mild monoamime oxidase inhibiting effects and is also found in some rauwolfia species too. But certainly other alkaloids found in such, like deserpidine (also a prescription drug), ajmaline (likely another prescription drug) and rescinnamine (yet another prescription drug that is actually angiotensin converting enzyme inhibitor), appear to have the opposite effects.  And while rauwolfia serpentina is one of the most important herbs in Traditional Chinese Medicine (known as "shegen mu" or "yindan shemu"), that does not mean it is legal to sell as a dietary ingredient in a dietary supplement in the USA.

Not acceptable!

Ingredient #2 - N-Carbamylglutamate: The "Mass Builder"

Great research on this chemical shows that it significantly boosts muscle tissue development in mammal (pigs) via carbamylphosphate synthase-1 (an enzyme) needed to create arginine (J. Nutr. February 2007 vol. 137 no. 2). There is some likelihood that N-carbamylglutamate will also increase nitric oxide levels. This may contribute to a great pump effect and/or fuller feeling muscles.

At least one study has concluded that you only need maybe 12%-14% as much N-carbamylglutamate to get the same results as whatever you would see from L-arginine and likely its more common salts (Amino Acids.2010 Aug;39(3):831-9).

The biggest problem I can see with N-carbamylglutamate is that it is clearly a synthetic homolog of N-acetyl-glutamate. It is likely OK to use as a dietary ingredient in dietary supplements In the USA, N-carbamylglutamate is clearly an Orphan Drug approved as such by the FDA on 27-NOV-2012.

N-carbamylglutamate is thus a prescription drug which is marketed under the name Carbaglu® and is clearly not acceptable as a dietary ingredient.

Man Performing Dumbbell Rows
Research on N-Carbamylglutamate shows that it significantly boosts muscle tissue development in mammal (pigs) via carbamylphosphate synthase-1.

Ingredient #3 - Theacrine: The "Euphoric Stimulant"

Theacrine has a stimulant effect somewhat similar to caffeine but – subjectively – less dirty and more euphoric. Theacrine, based on data known at this time, does not appear to have the attenuating effects of caffeine with chronic use.

Just so we are crystal clear, I am discussing THEACRINE and not THEANINE, which is a different dietary ingredient that also is sometimes used in conjunction with caffeine. Theacrine is a prurine alkaloid that is actually similar in structure to caffeine. It is naturally found in theobroma grandiflorum which is a fruit bearing tree found endogenous to South America (as the name implies, the fruit has a vaguely chocolate-like taste) and camelia sinensis spp. assamica which is used to make tea in Northeastern India.

While theacrine itself was not found in a dietary supplement sold in the USA before October 15, 1994, and is thus not grandfathered in under DSHEA 1994, several researchers (and a company I am somewhat familiar with) have both commercially synthesized and studied this interesting compound extensively for use in humans. They have managed to obtain GRAS status for it (Generally Regarded As Safe) just last year in 2014.

As a stimulant I think it is an excellent compound as a stimulant. I have personally ingested 200mg of theacrine at a time. I like the way it makes me feel for sure. The one drawback is the cost of it right now as it is fairly expensive.

Compound Solutions, Inc., located in Southern California, sells the branded Teacrine® version. This is a highly pure, "best quality" bioidentical compound to that found in the botanicals. I think caffeine and theacrine together will end up being a mainstay "stimulant stack" in dietary supplements in the near future.

Notice of disclosure: I do not and have not used theacrine in any formulation I have worked on and commercialized to date. I derive zero money or any other financial benefit from any type of theacrine, including Teacrine® as a branded ingredient.  I have no pending or awarded IP related to theacrine in any venue.

Ingredient #4 - Yohimbine Hydrochloride: The "Stimulant & Fat Loss Aid"



Why supplement companies use it: has a very obvious peripheral, stimulating effects, putative fat burning effects, also has some vasodilating properties and may be useful in treating erectile dysfunction. This compound has been "around" seemingly forever.

But I am going to drop a heck of a bombshell here.

I do not think it is legal to sell yohimbine hydrochloride (the salt) as a dietary ingredient for use in dietary supplements.

First, it is currently sold as a prescription drug under the brand names Yocon®, Testomar® and formerly as Aphrodyne® - typically as tablets that contain 5.4mg of yohimbine hydrochloride salt. So in order for yohimbine hydrochloride to be even remotely considered acceptable for sale as a dietary ingredient it would need to be:
  1. Sold openly in the USA in a dietary supplement before October 15th 1994, or
  2. There would need to be a New Dietary Ingredient (NDI) application filed with the FDA after October 15th, 1994, but before yohimbine hydrochloride was sold as a prescription drug in the USA – something that is temporally impossible since yohimbine hydrochloride has been sold as a prescription drug in the USA since the 1930's to treat impotence, or
  3. The FDA would have grant an exemption to yohimbine hydrochloride and I can see zero evidence that such has happened by looking back in the Federal Register or on the FDA website.
Let's go back to scenario #1 for a moment. I can find zero evidence in my old magazines from the 1980's and 1990's that yohimbine hydrochloride was ever marketed in the USA as a dietary supplement. If someone has absolute evidence proving such like a magazine advertisement, please feel free to scan a copy of your evidence, send it in to enlighten me.

Sure, I see plenty of old, pre-1994ish advertisements in the muscle magazines for dietary supplements that contain (at least the label claims they did) "Yohimbe Bark Extract" (Pausinystalia johimbe). Some of these extracts even claim to contain anywhere from 2%-5% yohimbine which is an indole alkaloid found in the bark of the aforementioned botanical and has been used for decades as a folk remedy for impotence, for "energy" and so forth.

So OK, if you see "Yohimbie Bark Extract" or "pausinystalia johimbe" or perhaps even "yohimbine" on a supplement facts panel there is a chance it may be acceptable as a dietary ingredient. However, the salt, specifically yohimbine hydrochloride is:
  1. Not naturally occurring in any plant, animal, food stuff, etc., that I know of and
  2. Absolutely is sold as a prescription drug in the USA.
There may not be much in the difference – clinically speaking – regarding how Yohimbe Bark Extract or "pausinystalia johimbe" or plain old yohimbine (no salt) makes a person feel versus yohimbine hydrochloride (salt). But that is not the point! The chemical yohimbine hydrochloride is absolutely considered a prescription drug per FDA! So while there may be some merit in that Yohimbe Bark Extract or pausinystalia johimbe or plain old yohimbine, are they acceptable as dietary ingredients? The hydrochloride salt of yohimbine is likely not.

Now before you write and blast me about how FDA's Draft Guidance Document about what is or is not a dietary ingredient, because it reads salts of dietary ingredients that hydrolyze in water possibly being OK for use as dietary ingredients, remember…yohimbine hydrochloride is SPECIFIED as a prescription drug. If you wanted to manufacture and sell yohimbine aspartate or some other non-hydrochloride salt? That might be acceptable as a dietary supplement – maybe.

And just because yohimbine hydrochloride has been sold openly – albeit incorrectly mislabeled – as a dietary ingredient in some supplements for a very long time does not mean it is legal and does not mean the FDA won't crack skulls over it when they decide they are ready to. Not acceptable!

Beefy Bodybuilder
Enobosarm/Ostarine is a bona fide 100% synthetic selective androgen receptor modulator (SARM) and is absolutely is anabolic!

Ingredient #5 - ((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluormethyl)pheny;]-2-hydroxy-2-methylpropanamide: The "Anabolic SARM"

This is a bona fide 100% synthetic selective androgen receptor modulator (SARM) and is absolutely is anabolic! You may also know this chemical by its more common names – Enobosarm and Ostarine!

This compound is absolutely banned and tested for by WADA and likely many other testing entities. What's worse, is the drug (and it 100% absolutely is a drug) is not yet approved for sale yet even as a prescription drug and the clinical testing on it in humans only goes up to about 3mg per day over a 12 week period.

There are companies selling Ostarine in capsules that have 10mg per capsule, which is more than 3X the amount given to humans in the clinical studies. This is really insane and considering the way consumers in our industry tend to think, its very likely that people might opt for the "more is better" approach and end up taking 2-3 capsules per day as one company foolishly advertises right on their label for users to take up to 3 capsules (10mg in a capsule or 30mg total!) per day which is 10X the dose used in the human study.

What's worse is that even in the human study, using only 3mg per day (for 12 weeks – see here) clearly demonstrate that there is some liver toxicity with 3mg dose (ALT enzyme levels rose around 20%) so one can only imagine what 30mg will do to your liver at least on a temporary basis. This is really uncharted territory here. So obviously this is not a dietary ingredient and it's highly likely that it never will be. And it can't legally be sold in a dietary supplement.

Furthermore, aside from the FDA (and maybe the DEA per the new DASCA 2014 law) going ballistic when they finally catch up with this? I see the drug company GTx that is developing this as a prescription drug likely litigating for patent infringement against some of these "supplement companies" selling this – clearly in violation of federal law – as a dietary supplement. Not acceptable!

Ingredient #6 - Theophylline: "The Profound Stimulant"



This chemical cousin to caffeine has a profound stimulant effect, especially noticeable at the cardiopulmonary level as well as in the CNS.

Theophylline is a natural metabolite of caffeine in humans,. About 4% of the caffeine a healthy person ingests is metabolized into theophylline (theobromine and paraxanthine are other important stimulant metabolites of caffeine). Theophylline is natural found in cacao beans (Theobroma cacao) and in a variety of tea types (Camelia sinensis) at levels that would be extractable (close to 4mg/g naturally in the case of some types of cacao beans). In fact, various botanical extractions containing 30%-50% w/w of naturally occurring theophylline are readily available from several Asian countries at prices that make them feasible ingredients for dietary supplements (note – these teas likely contain high levels of other, stimulant methylxanthines like caffeine and theobromine too).

Theophylline and some of its salts have also been sold – and still are although they have generally fallen into disuse recently – as prescription drugs for use in treating COPD and asthma. Some of the brand names are Elixophyllin®, Theo-Dur®, Slo-Phyllin®, Uniphyl® and so forth.

This presents sort of a conundrum here – from a regulatory standpoint is it possible to have something be a prescription drug and a dietary ingredient. The obvious answer is "yes" for many reasons beyond the scope of this article, but in this particular case some clarification is in order.

First, any of the salts of theophylline that are sold as prescription drugs are likely to be verboten as a dietary ingredient. They are not naturally occurring and not metabolites of something found in food. Next, you'd be hard pressed to find proof that they were ever sold before October 15th 1994 in a dietary supplement.

But the base, anhydrous theophylline, what about that? My layman's opinion is that making a claim on a label and using 99.9% synthetic, anhydrous theophylline as a dietary ingredient is probably going to raise the eyebrows of some folks at FDA. I am absolutely sure that various teas and cocoa/chocolates containing theophylline were sold before October 15th 1994 as dietary ingredients.

So…if the theophylline content is derived from a tea or from cocoa/chocolate or some other botanical source that was clearly sold before that date? It may be OK. Since legit extracts and concentrates exist (there are even now botanicals that contain caffeine with levels exceeding 80%!) that contain 30%-50% theophylline those extracts may be considered "kosher" for use as dietary ingredients. They would need a statement of identity to clarify such clearly in a supplement facts panel though.

Allow me to provide an example. I know that the Criollo variety of cocoa beans (Theobroma cacao) from Venezuela have something close to 4mg/g theophylline content naturally. A simple water percolation (extraction) can easily bring this up to 80mg/g when the extraction solvent (water) is evaporated away. That's 8% theophylline just by "brewing it and drying it out" – more elaborate extractions will easily allow this to exceed 30%!  And this does not include the caffeine, theobromine, paraxanthine, etc., that will likely be pulled with the theophylline.

So…while listing "theophylline" on the label might be a no-no, if you purchased Criollo Cocoa Bean extract (Theobroma cacao) that contained 30%-50% theophylline? That would likely be perfectly acceptable to see on the supplement facts. Thus, on this ingredient I am inclined to think it's acceptable so long as it is absolutely derived from a botanical source that was grandfathered in before October 15th 1994.

This one?  OK as discussed!

sugar
Sugar snobs believe Highly Branched Cyclic Dextrin (HBCD) is far superior to plain maltodextrins.

Ingredient #7 - Highly Branched Cyclic Dextrin (HBCD): The "Superior Sugar"

HBCD is a fancy-pants sounding carbohydrate source that "sugar snobs" (I feel erroneously) believe is far superior to plain maltodextrins due to "higher osmolarity" (cough, cough!) of HBCD.

Because most people do not understand the difference between osmolarity, osmolality and tonicity, the pseudo-science chatter on the internet that "good brahs" parrot when they get their "expert certs" means this material is considered "solid." There is nothing wrong with it and its fine as a carbohydrate source – it tastes pretty mild and in concentrations most would mix into water it works well. It's just at least 15X the cost of a high DE rated maltodextrin, which I feel will do – more or less -  the same thing (if you understand that not all sugars are bad, you would realize there are some sugars that are even better than HBCD's and maltodextrins depending on how and what you use them for – I am going to write an elaborate piece on carbohydrates and their use in our industry soon which debunks the nonsense soon, I promise!).

So HBCD is a snob's carb. Of course it's OK for use as a dietary ingredient, right? WRONG!  HBCD's are SYNTHETICALLY derived by enzymatic re-arrangement of amylopectin. HBCD is NOT NATURALLY OCCURRING. Because HBCD's are considered "chemically modified" amylopectins, they would not normally be acceptable as a dietary ingredient on their face.

However, one company in Japan has managed to make their HBCD GRAS by self-affirmation (perfectly legal & acceptable) so long as the dose does not exceed 25g per day. So yes, this is OK (apparently up to 25g per day) for use as a dietary ingredient. However, just remember that HBCD is considered as synthetic as any artificial sweetener or flavor from a legal standpoint, in my opinion.

So any company adding this to their dietary supplement may have an actionable, legal issue in the form of a class action lawsuit if they claim the supplement is free from artificial ingredients.  I have seen at least two companies using HBCD in their supplement products while also making the "contains no artificial x, y, z's" – and that is likely to be viewed as consumer fraud.  There is nothing wrong with HBCD's, and they are perfectly fine for use as a carbohydrate source, so long as you understand they legally should not be more than 25g of what you ingest and that they are indeed "artificial." However, OK in the USA as a dietary ingredient.

As a notice of disclaimer, I have significant awarded and pending IP holdings in the USA related to a different carbohydrate, isomaltulose.

Editor's note: Bruce Kneller is the Chief Formulator for Giant Sports Supplements. Tiger Fitness stocks the complete line of Giant Sports products. Click here to purchase supplements from this top quality line.