HerbalEGram: Volume 9, Number 6, June 2012

Controversy over the origin and effects of the compound 1, 3-dimethylamylamine (DMAA) has been building since it was reintroduced under the trademark Geranamine^® (Proviant Technologies; Champaign, Illinois) in 2005. Claimed by some to be a component of the geranium plant (Pelargonium graveolens), this once-obscure chemical 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 the Nutrition Business Journal.¹ However, in recent years, reports of adverse events associated with DMAA-containing supplements have brought the compound’s safety into question. ^1,5,8

A Brief History of DMAA

DMAA — a substance known by many names including methylhexaneamine (MHA) and 2-amino-4-methylhexane — was first introduced in the 1940s by Eli Lilly & Co. and trademarked in 1971 as a nasal decongestant under the brand name Forthane. By the 1980s, the patent had expired and the drug was all but forgotten until it was reintroduced as a dietary ingredient for use in dietary supplements in 2005 by Patrick Arnold — the organic chemist who served jail time for his involvement in the Barry Bonds BALCO steroids scandal of the early 2000s.²

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary supplement is considered adulterated unless its components are naturally occurring substances that existed in the human diet prior to 1994.³ Resorting to a single, infamous, and scientifically-dubious study by Ping et al. from 1996 that appeared in the discontinued Journal of the Guizhou Institute of Technology, Arnold introduced Geranamine (DMAA or MHA) as a naturally occurring constituent of geranium oil. The paper, which failed to adequately describe the researchers’ methodology, concluded that essential oil of geranium contained less than 1% DMAA (0.6% by weight) based on analyses by mass spectrometry and gas chromatography.⁴

Subsequent studies have failed to reproduce the results of Ping et al. 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.⁵

“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.¹ In fact, DMAA’s effects on animals has been documented for more than half a century. “In The Dispensatory of the United States of America 1950 Edition, DMAA’s systemic toxic effects in animals was described as ‘greater than that of ephedrine and less than that of amphetamine,’” he added.

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.⁹ 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.¹⁰ “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.”

Health Canada — the Canadian equivalent of FDA — banned DMAA from supplements in 2011, concluding that “there is no credible scientific evidence that DMAA is captured as an isolate of a plant.”⁶ And beginning 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.⁷ This requirement, which applies only to products containing DMAA, went into effect on January 13, 2012.

In February 2012, however, USPLabs, the Dallas, Texas, company that sells the popular DMAA-containing pre-workout supplements Jack3d^® and OxyElite Pro^®, presented an unpublished 69-page document summarizing the results of 7 clinical studies in support of their products’ safety.⁸ “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.”

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.¹¹

On the surface, the controversy over DMAA in supplements mirrors the ephedra (Ephedra sinica) 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. According to Dr. Cohen, this would be the "easiest, least costly and least prolonged" path, he said in a recent article in the Chicago Tribune.¹² "I think they recognize that it's an unsafe ingredient.”

—Tyler Smith

References

1. Cohen PA. DMAA as a dietary supplement ingredient. [research letter] Archives of Internal Medicine website. Available at: http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinternmed.2012.1677. Accessed May 30, 2012.

2. Shipley A. Chemist's new product contains hidden substance. The Washington Post. May 7, 2006. Available at: http://www.washingtonpost.com/wp-dyn/content/article/2006/05/07/AR2006050700913.html. Accessed May 28, 2012.

3. New Dietary Ingredients in Dietary Supplements - Background for Industry. US Food and Drug Administration website. Available at: www.fda.gov/Food/DietarySupplements/ucm109764.htm#whatis. Accessed June 1, 2012.

4. Ping Z, Jun Q, Qing L. A study on the chemical constituents of geranium oil. Journal of Guizhou Institute of Technology. 1996. 25(1):82-85.

5. Use of Recreational Drug 1,3-Dimethylethylamine (DMAA) Associated With Cerebral Hemorrhage. Annals of Emergency Medicine website. Available at: www.annemergmed.com/article/S0196-0644(12)00374-5/abstract. Accessed June 1, 2012.
 

6. Daniells S. Health Canada: DMAA is not from geranium. NutraIngredients USA website. Available at: www.nutraingredients-usa.com/Industry/Health-Canada-DMAA-is-not-from-geranium. Accessed May 28, 2012.
 

7. Code of Ethics and Business Conduct. American Herbal Products Association website. Available at: www.ahpa.org/Portals/0/pdfs/AHPA_CodeOfEthics.pdf. Accessed May 31, 2012.

8. Bloomer RJ, McCarthy CG, Canale RE, Alleman RJ, Reed JP, Farney TM et al. A compilation of clinical safety studies evaluating DMAA. February 1, 2012 [unpublished data].

9. FDA challenges marketing of DMAA products for lack of safety evidence. [press release] US Food and Drug Administration website. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302133.htm. Accessed May 31, 2012.
 

10. FDA warns DMAA marketers. Natural Products Insider website. Available at: www.naturalproductsinsider.com/news/2012/04/fda-warns-dmaa-marketers.aspx. Accessed May 31, 2012.
 

11. Slideshow: DMAA’s litigious past. Natural Products Insider website. Available at: www.naturalproductsinsider.com/galleries/2012/06/slide-show-dmaas-litigious-past.aspx. Accessed May 30, 2012.
 

12. Deardorff J. Pressure builds to ban dietary supplement DMAA: Critics cast doubts on safety of popular energy booster. The Chicago Tribune. June 4, 2012. Available at: www.chicagotribune.com/health/ct-met-dmaa-supplements-20120604,0,7629843.story?page=1. Accessed June 4, 2012.