[Editor’s note: This article has been updated and expanded from a previous version that appeared in the June 2012 issue of ABC’s HerbalEGram.]

Controversy over the origin and effects of the compound 1,3-dimethylamylamine (DMAA) has been building since it was reintroduced as a dietary ingredient for use in dietary supplements in 2005.¹ The chemical was trademarked as Geranamine^® (Proviant Technologies; Champaign, Illinois) based on the supposition that it was a naturally occurring component of the sweet-scented geranium, also known as the rose geranium (Pelargonium graveolens, Geraniaceae) — a claim supported by a single, unverified scientific paper from 1996 published by Ping et al. in the now-defunct Journal of the Guizhou Institute of Technology.²

In recent years, DMAA has become a popular component of pre-workout supplements for its stimulant-like effects. Sales of such supplements reached $100 million dollars in 2011, according to Nutrition Business Journal.³ However, worldwide reports of adverse events associated with DMAA-containing supplements have brought the compound’s safety — and origin — into focus.

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary supplement is considered adulterated unless its constituents are naturally occurring substances that existed in the human diet prior to 1994.⁴ Recent studies, however, have failed to detect DMAA — otherwise known as methylhexaneamine (MHA) — in authenticated samples of geranium oils, stems, and leaves.^5,6

New Evidence

In July, researchers from the University of Texas at Arlington used a molecular analysis technique to determine the natural or synthetic origin of DMAA in 13 supplements purchased from various outlets including GNC stores and Amazon.com.⁵ Due to the chemical structure of DMAA, the molecule has 4 forms, or isomers, 2 of which are non-superimposable mirror images of each other.

In nature, molecules with multiple isomeric forms usually exist in a single dominant form — often referred to as right-handed or left-handed. “For example, we’re comprised of left-handed amino acids exclusively,” explained Daniel W. Armstrong, PhD, lead author of the recent paper, which appeared in Drug Testing and Analysis (oral communication, July 13, 2012).

By comparing the unique ratios of the chemical forms of DMAA in the 13 consumer supplements to 2 synthetic DMAA standards purchased from analytical chemical reference standards suppliers Sigma-Aldrich (Milwaukee, WI) and ChromaDex (Irvine, CA), Armstrong determined that it is “unlikely that the DMAA in supplements originates from natural sources such as geranium oils” because the chemical ratios of DMAA in the supplements were indistinguishable from the synthetic forms of the chemical, both of which contained equal amounts of the two non-superimposable isomers — a strong indication of the molecule’s synthetic origin.⁵ This analysis remains the only scientific investigation thus far to systematically evaluate the various chemical forms of DMAA in order to determine the true origin of the compound.

A study published in June in the Journal of Analytical Toxicology provides further evidence of DMAA’s synthetic origin.⁶ “The bottom line is that those products on the market, whatever is there, are synthetic, not natural,” said lead author Mahmoud ElSohly, a professor in the School of Pharmacy at The University of Mississippi (oral communication, June 5, 2012).

The study, supported in part by the US Anti-Doping Agency (USADA), analyzed 20 commercial geranium oils, 3 authenticated geranium oil samples, as well as botanically vouchered samples of geranium leaves and stems for the presence of MHA (DMAA). Each authenticated sample was derived from P. graveolens, not to be confused with species from Geranium, an entirely separate genus.

Authenticated leaves and oil of P. graveolens were obtained from the Indian Institute of Integrative Medicine, a natural products research organization based in Jammu, India. Additional leaves and stems were obtained from the medicinal plants garden at the National Center for Natural Products Research at the University of Mississippi. “All authenticated samples (plant material and volatile oil) were analyzed for MHA by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS-MS) and liquid chromatography high-resolution mass spectrometry (LC-QTOF-MS) methods,” the authors explained in the paper.⁶

None of the samples, authenticated or commercial, was found to contain MHA. “The data show that none of the authenticated P. graveolens essential oils or plant material, nor any commercial volatile oil of Pelargonium (geranium oil) contain MHA at detectable levels (limit of detection: 10 [parts per billion]),” the study concluded.6

For comparison purposes, researchers also measured the amount of DMAA in 3 MHA-containing dietary supplements purchased from GNC.com on December 1, 2011. “The dietary supplements that contained MHA as one of their ingredients (allegedly from geranium or geranium stems) contained large amounts of MHA,” the authors wrote. “All of these products contained more than 1 mg MHA per g of dietary supplement. Each of the supplements contained more than 250 g of supplement material per bottle, which would require at least 250 mg of MHA per bottle of supplement.”⁶

A simple calculation by the authors shows that this amount of MHA could not possibly be extracted from true geranium samples. “If MHA were to be present in the oil at 0.6% (i.e., 6mg MHA/mL oil), as reported [in the Ping et al. paper], and assuming that the leaves yield 0.1% oil, it would require approximately a kilogram of leaves to be harvested to prepare 6 mg of MHA. … [One] bottle of 100 capsules would require the processing of 167 kg [~370 lbs] of P. graveolens leaves for 167 mg of geranium oil!”6

American Botanical Council (ABC) Founder and Executive Director Mark Blumenthal issued a statement in an interview with NutraIngredients shortly after the publication of Dr. ElSohly’s paper (M. Blumenthal email to S. Daniells, June 26, 2012). “ABC has stated repeatedly that we have not seen any credible, published scientific evidence that DMAA (MHA) is found or detectable in Pelargonium graveolens,” he wrote. “The results of this new analysis further strengthen ABC’s previously-stated position. It may be seen as another nail — a big one — in the coffin of the DMAA-from-plants claims controversy.”

Organizations Take Action

The US Food and Drug Administration (FDA) became involved in the DMAA controversy on April 24, 2012, when it sent letters to 10 companies warning them that their DMAA-containing supplements are considered adulterated until they file a new dietary ingredient notification.⁷ The companies were given 15 business days to respond with details on how they plan to address the situation.

“Before marketing products containing DMAA, manufacturers and distributors have a responsibility under the law to provide evidence of the safety of their products,” Daniel Fabricant, PhD, director of FDA’s Dietary Supplements Program, is quoted as saying in an article from Nutraingredients-USA.com.⁸ ”DMAA is known to narrow the blood vessels and arteries, which can elevate blood pressure and may lead to cardiovascular events ranging from shortness of breath and tightening of the chest to heart attack.”

In 2011, Health Canada — the Canadian equivalent of FDA — banned DMAA from supplements, concluding that “there is no credible scientific evidence that DMAA is captured as an isolate of a plant.”⁹ An unpublished paper from Health Canada titled “Classification of 1,3-Dimethylamylamine (DMAA)” concludes, “Given the errors in the Ping et al. (1996) paper and the fact that these authors did not fully isolate and characterize DMAA, together with the contradictory information from numerous other peer-reviewed scientific studies which show no natural occurrence, [the Natural Health Products Directorate] and [the Therapeutic Products Directorate] have jointly concluded that 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 (NHP)]” (R. Marles, email, June 4, 2012).

In 2009, after reports of panic attacks, seizures, and stress-related heart attacks associated with supplements containing DMAA, the substance was added to the World Anti-Doping Agency’s (WADA) list of banned in-competition substances. The same year, a brain hemorrhage in a 21-year-old male in New Zealand was reported after use of DMAA as a party drug in combination with alcohol and caffeine.¹⁰

“Causality has yet to be proven, but these adverse events are consistent with DMAA’s known pharmacologic actions,” wrote Pieter A. Cohen, MD, in a research letter published online in May 2012 in the Archives of Internal Medicine.³

In December of last year, following the deaths of 2 soldiers who used supplements with DMAA, the US military removed all such supplements from military exchanges around the world. Further, the American Herbal Products Association (AHPA) issued an alert in the form of a trade requirement to member organizations in August 2011 warning them not to label DMAA as a constituent of geranium oil due to the lack of acceptable evidence.¹¹ This requirement, which applies only to products containing DMAA, went into effect on January 13, 2012.

However, USPLabs, the Dallas, Texas company that sells the popular DMAA-containing pre-workout supplements Jack3d^® and OxyElite Pro^®, cites data from 7 short-term clinical studies — all of which are available on the company’s website in support of their products’ safety.¹² “Each study has shown that although DMAA can produce a mild and transient increase in systolic blood pressure, no other safety variables are affected,” the authors wrote in the report. “Kidney and liver function are unaffected and no serious adverse events are reported in any of the studies. These data clearly demonstrate that the dietary supplements Jack3d and OxyElite Pro which contain DMAA, are safe when used as directed and following all label directions and warnings.”

Further, USPLabs has alerted the media of a forthcoming paper in Analytical Chemistry Insights, which the company claims will confirm the presence of DMAA in geranium plants obtained from China.13 The paper was not available at press time.

The Future of DMAA

Beginning in November 2011, class action lawsuits were filed against Florida-based supplement maker BPI Sports, alleging that its supplements contained unlabeled DMAA, which, according to the suit, has potentially life-threatening side effects. In February 2012, the law firm Abbey, Spanier, Rodd & Abrams LLP filed a class action lawsuit against supplement giant General Nutrition Centers (GNC), alleging it has been selling products with “wholly synthetic” — and therefore adulterated — DMAA.¹⁴

More recently, several countries have issued alerts warning consumers of the potential dangers of the chemical. Nutraingredients.com reported in July that the Therapeutic Goods Administration (TGA) of Australia added DMAA to its Schedule 9 list, which criminalizes the sale, distribution, use, or manufacturing of the chemical.¹⁵ In June, the Food Standards Australia New Zealand (FSANZ) released a consumer warning about DMAA-containing sports supplements. “DMAA has been linked in other countries with various adverse health effects including high blood pressure and vomiting,” said FSANZ Deputy Chief Executive Office, Melanie Fisher, in the organization’s consumer warning. ¹⁶ “Regulatory agencies are working together to assess the products’ safety and are currently seeking the assistance of retailers, importers and distributors on a withdrawal of the products.”

Also in June, the Finnish Food Safety Authority, Evira, followed Sweden and Denmark in clearing the market of DMAA-containing supplements. According to Evira, “Risk assessment by the Danish and Swedish Food Safety Authorities has concluded that DMAA is not appropriate for human consumption due to its associated health risks.”¹⁷

In an article published on July 2, 2012, Natural Products Insider reported that some American insurance companies that provide liability coverage to the dietary supplement industry are beginning to reconsider their coverage of DMAA.¹⁸ Greg Doherty of Poms & Associates Insurance Brokers, Inc., which has experience in the supplement industry, explained the new development. “Two carriers will now exclude it,” he said in the article. “As of right now, coverage is still available for DMAA products from other insurers, but my opinion is that the window is closing. It’s really the ephedra insurance coverage story all over again.”

On the surface, the controversy over DMAA in supplements mirrors the ephedra (Ephedra sinica, Ephedraceae) debate from nearly a decade ago. Supplements containing ephedra were linked to dozens of instances involving heart attack, sudden death, and stroke. FDA banned ephedra in dietary supplements in 2004, and some industry experts speculate whether the DMAA debate will follow the same path. One of the main differences, however, between the DMAA and ephedra situations is that the primary active alkaloids ephedrine and pseudoephedrine found in the ephedra plant (ma huang in Chinese) are clearly plant-derived ingredients, whereas DMAA has not been confirmed to be a plant-derived compound.

Dr. Cohen, as part of his commentary in the Archives of Internal Medicine, suggested a simple alternative to an extended, impassioned argument — a formal FDA ban on the substance. This would be the “easiest, least costly and least prolonged” path, he said in a recent article in the Chicago Tribune.¹⁹ “I think they recognize that it’s an unsafe ingredient.”

Editor's note: At press time, a new analytical paper by Li et al. (2012) was published in which the authors claim to have found traces of DMAA in samples of oil of geranium at levels of parts per billion (ppb). ABC will post a commentary on its website discussing this paper.²⁰

References

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