Time to act on unauthorised DMAA-geranium sports products in Europe?

By Shane Starling

- Last updated on GMT

Related tags Food and drug administration Dmaa

Jack3d: Contains 1,3-dimethylamylamine, which in Italy at least, is not authorised for use in food supplements
Jack3d: Contains 1,3-dimethylamylamine, which in Italy at least, is not authorised for use in food supplements
Sections of the European botanicals industry are beginning to raise red flags about DMAA, the synthetic stimulant commonly found in sports supplements but often labeled as an extract of geranium plants.

DMAA, which commonly goes by other names including 1,3-dimethylamylamine and methylhexaneamine (MHA), is not authorised for use in food supplements in the European Union, but is included in many weight loss and body building products – usually labeled as geranium extracts.

Products like USPLabs’ ‘Jack3d’ are being sold on many retail websites across the EU even though the product lists 1,3-dimethylamylamine on its ingredients panel, which it states is derived from ‘geranium stem’.

The situation prompted one Italian-based commentator at the recent NUCE trade event in Milan to wonder why authorities in his country are not taking some form of action.

“Of course the problem is that DMAA and geranium oil – even the natural form – cannot be used in Italy in food supplements,”​ he said. “But nothing is being done so far.”

Jack3d, which boasts it can, “produce an intense sensation of drive, focus, energy, motivation & awareness”​ and “allows for rapid increases in strength, speed, power and endurance” ​is being sold for around €30 on Italy’s second most popular online retail site for food supplements.

The situation is known to be under investigation by at least one European trade body and it has crossed the radar of the EU-funded botanical research project, PlantLIBRA.

Source

There is an ongoing debate, especially in North America, about whether DMAA, first manufactured synthetically by drug giant Eli Lily in the 1940s and trademarked as Forthane in 1971, is in fact a constituent of geranium, with the consensus growing that it is not.

Health Canada in August issued a statement that DMAA is not found naturally in geranium in affirming that any products containing it require a drug authorisation. But the US Food and Drug Administration (FDA) is yet to act on the matter, whilst trade groups are conducting research of their own.

While the legality is somewhat grey, the labeling practice hinges on the fact that a natural substance may be permissible in food supplements; a synthetically manufactured substance not so unless it has an explicit authorization. Yet in many jurisdictions, including the US, natural extracts also require authorisations.

Doping

DMAA and geranium extracts are banned by the World Anti-Doping Agency (WADA) and there have been doping violations, some of which are in process, and which may bring the possible adulteration issue to the public eye at greater intensity than has occurred to date.

US tennis professional Robert Kendrick was banned for 12 months earlier this year after testing positive for ‘geranium’ after taking a Jack3d-like product containing 1,3-dimethylamylamine.

"This is being sold as an otherwise safe and legit dietary supplement," ​said Travis Tygart, head of the US Anti-Doping Agency (USADA), of DMAA. "It's not. It's had tragic results to athletes. And there's a whole population of consumers who have no clue."

Many in industry would like to see DMAA removed from products because they fear misuse of the potent stimulant may lead to serious injury as happened with another potent herbal stimulant, ephedrine, before the US FDA banned it in 2003. It remains banned in most countries.

However, a search of the FDA adverse event report (AER) database reveals no DMAA-linked events in 2008 and 2009.

Present in geranium?

According to a single analysis by Chinese researchers reportedly using gas chromatography – mass spectrometry (GC-MS) techniques and published in the Journal of Guizhou Institute of Technology (1996, Vol. 25, pp. 82-85), DMAA is a constituent of geranium oil, but no other published analysis has reported its presence.

Health Canada criticised the Chinese paper for containing ‘errors’, and noted at least seven other papers found no DMAA in geranium oil.

The agency said, “there is no credible scientific evidence that DMAA is captured as an isolate of a plant … and therefore cannot be classified as a natural health product.”

Ed Wyszumiala, the general manager of dietary supplement programs at NSF International, told NutraIngredients-USA at the time: “This again shows that DMAA is an active pharmaceutical ingredient (API) and not a dietary ingredient.”

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Response Anthony A

Posted by Supplement Expert,

I have been following this geranium/DMAA issue for a while now and I must say I have been very surprised by the lack of objectivity and investigation.

For example, you stated, "If DMAA was a SYNTHESIZED ingredient one would expect to find nearly equal ratios between the two forms that comprise each pair - this is seen in the single pairs that comprise dl-lipoic acid and dl-methionine. The nearly equal “racemic” ratio is irrefutable evidence that it was not derived from a biological source but from chemical synthesis."

You said that a racemic mixture is "irrefutable evidence", that something isn't derived from a biological source but from chemical synthesis, but this is unequivocally false to those that are knowledgeable in the areas of natural products chemistry and pharmacognosy. Racemates do in fact occur in nature and this is well established in the scientific literature. In fact, there is at least one racemate (i.e., nerol oxide) that has been confirmed in the geranium plant itself.

Below I have pasted several links to abstracts, full-text papers and even a book which clearly demonstrate and discuss that racemates are found in plants. The last link is to a paper which discusses the findings of the previously mentioned racemate in geranium oil.

http://www.ncbi.nlm.nih.gov/pubmed/20704409

http://www.ncbi.nlm.nih.gov/pubmed/19418361

http://www.ncbi.nlm.nih.gov/pubmed/19194839

http://www.if-pan.krakow.pl/pjp/pdf/2008/4_439.pdf

http://www.iupac.org/publications/pac/pdf/2005/pdf/7711x1943.pdf

http://www.ncbi.nlm.nih.gov/pubmed/19089827

http://www.ncbi.nlm.nih.gov/pubmed/19023875

http://www.sciencedirect.com/science/article/pii/003194229183763B

http://www.sciencedirect.com/science/article/pii/S0031942200863918

http://www.sciencedirect.com/science/article/pii/S0031942296008850

http://ddr.nal.usda.gov/bitstream/10113/9903/1/IND44003486.pdf

http://www.ncbi.nlm.nih.gov/pubmed/18596662

http://www.ncbi.nlm.nih.gov/pubmed/17191801

http://www.ncbi.nlm.nih.gov/pubmed/18473468

http://www.ncbi.nlm.nih.gov/pubmed/10552622

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Response to James K

Posted by Supplement Expert,

Yet again, I have noted a lack of objectivity and logic with these arguments.

A brief recap of your remarks is illustrative. You stated, "Reviewing 25 years of geranium oil research and having almost 20 myself, I can say that there is no mention of this compound in geranium oil. The paper from 96 has so many critical analytical errors that jump out to those of us experts in the analysis of EO's. I have never seen a sample that did not have the racemic synthetic form in it. I have not seen this compound in any natural product."

And:

You stated, "After 20 years of analyzing geranium oil and my recent review of 25 years of papers on the EO profile of geranium oil, I never observed this compound in it. Besides, the amine would be so stinky it would never smell like "rose geranium" it would smell like "bloated dead salmon geranium." The paper I had translated showed major errors by the author and no other peer-reviewed publication supported this finding. All DMMA samples I tested were synthetic, which can be easily determined by profiling the isomers (there are four chiral centers on the compound and on a standard GC column you get two peaks. You could get four peaks on a chiral column if you have the right phase selectivity.) There are a lot of compounds in this class that could take the place of this as there are with other API classes we test."

So, after reviewing 25 years of geranium oil research, you have never seen DMAA in geranium oil. That may be true, but not for the reasons you suggest. I'm not sure about you, but out of every paper I have reviewed, not one single paper has ever identified 100% of the components present in geranium oil. And how many of those papers used geranium oil from China? And out of those, how many were obtained from the same area as the Ping study? I found the answer was zero. I believe that if you run the published papers through these questions, you'll quickly find that there are none that can truly serve as a useful indicator as to whether or not DMAA occurs in the oil. It is beyond dispute that the conditions of analyses, the processing of the oil, the origin of the oil, as well as the geographic location and environment from which the plants used for making the geranium oil are obtained all create extremely divergent results. Consequently, I don't know how anyone can justify a conclusive assertion that DMAA is not present in geranium oil.

In fact, given that it is not well suited for GC analysis at relatively lower concentrations in a complex matrix (i.e., GC conditions must be just right regarding temp, injection and solvent delay or you will not detect DMAA; this has been noted in a published paper), it makes sense that these other papers didn't find it. During my own investigation, I have noticed that aside from the fact that every published paper has never been able to determine 100% of the compounds present, I was surprised to see there is such a tremendous amount of variation in the major components, not to mention the minor components of geranium oil. In fact, there is one paper demonstrating that even within the same country, major constituents are present in one sample and absent in another!

In addition, when I cross-referenced every published paper available regarding geranium oil analysis, I found that there were at least 5 compounds which have only been reported once and in no other papers. This is the same situation as that with DMAA, so I have a hard time understanding bold assertions that DMAA could not possibly be found in the oil.

Consequently, I don't find it hard to believe that a sample of geranium plant from a specific area in China contained a compound that A) may be more prevalent or in higher concentrations in samples from certain areas versus others, B) may present difficulties for analysis in the geranium oil matrix.

Also, you state that, “I have never seen a sample that did not have the racemic synthetic form in it, but I must say, if DMAA occurs in nature as a racemate, how can one justify a conclusive statement that it is synthetic?

I'm not really sure what to make of statement regarding there being no way that DMAA is present in rose geranium oil because if it did, it would smell like, "bloated dead salmon"?

It is beyond dispute that humans simply cannot detect potentially low levels of a compound, especially if it's in a complex matrix of strong odiferous compounds. This is why we have analytical instruments.

It's why, even though I'm snacking on some cherry Twizzler bites, washing it down with a red wine, I don't smell the sulfur dioxide present, which would be like rotten eggs. It's why the meat I'm about to eat that has sodium acetate as a preservative doesn't smell like vinegar. It's the same reason you wouldn't be able to smell a drop of bleach placed into a swimming pool or the reason you can't smell DMAA in a container of rose scented geranium oil.

Our noses aren't analytical instruments capable of getting down to such low levels, especially in a matrix of other compounds.

I thought I would also pass along some relevant notes from different papers that I have read. This is from a book: Lis-Balchin M. Geranium and Pelargonium. History of Nomenclature, Usage and Cultivation. CRC Press 2002:

"Rose Geranium oil is a very complex product that contains hundreds of compounds, some being hydrocarbons (aliphatic, aromatic, monoterpenic, sesquiterpenic with different skeletons), and the others being oxygenated with alcohol, phenol, oxide, aldehyde, ketone, acid, ester and ether functional groups.", and "Only 30 compounds are regularly and individually present at more than 0.3 per cent of the oil; together they represent about 90 per cent of the essential oil and are sufficient to form the basis of the essential oil quality. The other components appear as traces, the correct identification of which is sometimes difficult, especially when sesquiterpenic hydrocarbons are concerned".

This is from a paper which also points out the issues relating to using GC for geranium oil analysis:

"However, in the case of GC the identification of chromatographic peaks is just carried out by means of comparison of retention times with reference compounds. This means that due to the complexity of the matrix, some of the components may not be identified." Journal of Chromatography A, 1114 (2006) 154–163

And below are some notes from a paper that was presented to me, meant to demonstrate that the origin and processing of the plant and subsequent oil must be considered:

It has also been shown that even within the same country of origin, the chemical composition of geranium oil can be influenced by location, drying of biomass prior to distillation, application of growth regulators, storage of the oil, presence of weed, wilt disease, and different climates along with transplanting date, leading to samples containing no detectable levels of a compound in one study, while another study does detect the compound (10,11). It has also been shown that each time, a particular geranium oil is evaluated, at least one or more compounds are found which are not found in other investigations (11-13). For example, it has been reported in one study that a principle compound, isomenthone, normally found in Pelargonium graveolens, was not detected, with the authors stating that, "growth regulators, shading, distillation, storage, weeds, leaf ontogency, drying and seasons all influence the chemical composition of Pelargonium species oil", with the authors further stating that, "Hence, such appreciable differences in chemical characters noted between the present data and published data may be attributed to the different environmental parameters associated with the different localities from where the plants were harvested" (14). Thus, if a compound which is considered a main and principle constituent is not always present in geranium oil samples from different locations, it seems unreasonable to conclude that the same can occur with potentially minor constituents like DMAA.
This notion, is yet again mentioned directly within the Jain et al., paper, when they state, "Significant work on geranium essential oil has been carried out in different parts of India and it was found that chemical composition is influenced by location, drying of biomass prior to distillation, age of the leaves, method of distillation, application of growth regulators, storage of oil, presence of weed, wilt desease, and the effect of the semi-arid tropical climate." More importantly, the study itself yet again demonstrates this principle even when using the same variety of the species. For example, the authors' data show that the oil derived from plants grown in the northern Indian plains had detectable amounts of heptan-2-one, heptan-2-ol, β-pinene, 1-8-cineole, photocitral-A, terpenen-4-ol, menthol, linalyl propionate, α-yalangene, citronellyl propionate, α-cadinene, (E)-β-farnesene, allo-aromadendrene, α-muurolene, geranyl-iso-butyrate, γ-elemene, citronellyl butyrate, γ-cadinene, δ-cadinene, (E)-nerolidol, citronellyl valerate, T-cadinol, α-cadinol, geranyl hexanoate, geranyl heptanoate, and geranyl octanoate, while the oil derived from plants grown in the southern Indian hills did not. Conversely, the oil derived from the plants grown in the southern Indian hills had detectable levels of camphene, terpinolene and α-cubebene, while the oil derived from plants grown in the northern Indian plains did not. Obviously such a level of variation even within the same variety of plant species, even when grown within the same country, demonstrates this continuing theme throughout all published papers focusing on the chemical composition of geranium essential oil.

In addition, relating to the processing methods, we further note that unlike the Ping et al., study which simply used steam distillation, the oil in the Kulkarni et al., study, was derived via hydro-distillation in a Clevenger-type apparatus, which, as was shown in the Babu & Kaul study, can create divergent chemical compositions of the oil as compared to steam distillation. For example, utilizing this technique, the compounds sabinene and α-terpineol were not able to be detected in the resultant oil, while these compounds were in fact able to be detected when using steam distillation (15).

In fact, this occurs in the Babu and Kaul study itself, with the authors noting that, "Some of the chemical constituents, viz. trans-2-hexenal, α-terpinene, terpinolene, α-ylangene, α-copaene, etc., which have been reported previously, could not be detected under these experimental conditions".

In addition, this same study also further supports the notion that how the oil is derived can also influence the chemical composition. For example, using a "water distillation", the compounds β-caryophyllene, citronellyl acetate, sabinene, limonene, p-cymene, geranyl-n-propionate, guaia-6,9-diene and geranial were not detected, while, on the other hand, the use of "water-steam distillation", did allow for these compounds to be detected.

In fact, this is noted within the Lalli et al., study itself as they reported the following, "Pelargonium graveolens oil obtained from plants growing in the Himalayan region of Uttaranchal contained citronellol (33.6%) and geraniol (26.8%) as the principal components. Other major compounds included linalool (10.4%), menthone (6.0%), citronellyl formate (6.9%), α-humulene (6.1%) and α-selinene (6.6%). In this study, the P. graveolens oil samples from SBG and WSBG produced very low levels of citronellol (0.4%), citronellyl formate (< 0.05%) and linalool (0.3%). Furthermore, geraniol, α-humulene and α-selinene were not present. Isomenthone, the principle compound in the P. graveolens (SBG and WSBG) oil samples, was not detected in the P. graveolens oil analyzed by Rana et al. Growth regulators, shading, distillation, storage, weeds, leaf ontogeny, drying and seasons all influence the chemical composition of Pelargonium species oil. Hence, such appreciable differences in chemical characters noted between the present data and published data may be attributed to the different environmental parameters associated with the different localities from where the plants were harvested."

Thus, if a compound which is considered a main and principle constituent is not always present in geranium oil samples from different locations, it seems unreasonable to conclude that the same can not occur with minor constituents, which was also noted in the Lalli et al, study.

Furthermore, the Gomes et al., study itself further lends evidence that processing methods can greatly influence the chemical composition when they note the fact that using an oven to dry the leaves, versus natural air-drying can greatly reduce the amount of virtually all compounds, including isomenthone by more than 80% due to the lower volatility of the compounds (DMAA is volatile). Specifically, they state, "Drying the leaves in an oven prior to extraction resulted in an oil that was poorer in all the considered compounds except for geranyl and 2-phenylethyl tiglates, the less volatile compounds. In fact, the contents of isomenthone decreased more than 80%, while the concentration of the tiglates doubled. On the other hand, the air-dried geranium oil was found to contain the highest content of linalool and geraniol, having though approximately the same amount of citronellol and esters as using fresh geranium leaves."

In summary, for the reasons stated, I respectfully suggest that your assertions are grossly overstated and not at all consistent with the published literature.

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DMAA

Posted by JONIE MCMEIN,

Recently my partner failed a drugs test as DMAA was present in his weight loss supplement and it was not on the label and should not have been. The result is he was banned from his sport and we have faced a massive bill to defend the case. For that reason we are suing both the manufacturer and supplier but we are still uncertain on DMAA. You seem to be extremely knowledgeable and wondered if there is any guidance you can give towards moving forward in our case. One area is the potential short-term and long-term problems that DMAA could cause. Also, no-one seems to wish to deal with these companies, I believe we are the first in the UK to sue therefore not many organisations obviously know how to deal with it. Really just looking for any help or assistance in your obvious field of expertise. thanks in advance for any help.

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