Troubles are mounting and shelf space is shrinking for 1,3-dimethylamylamine, a stimulant ingredient used in dietary supplements that could be related to the deaths of two U.S. Army soldiers and other adverse events.

The Department of Defense Dec. 6 temporarily banned at military exchanges globally the sale of the popular bodybuilding and performance enhancement ingredient.

The suspension of sales on military bases comes after regulators in Canada and New Zealand restricted access to the ingredient, and as some U.S. firms are changing how they market and label it.

The developing situation also could trigger an FDA review of the ingredient, which some in the industry compare to ephedra – an ingredient FDA banned in supplements in 2004 because of adverse events including heart attack, stroke, seizure and death. DMAA could be connected to the same types of adverse events, the actions of several foreign health authorities indicate.

Military Investigates Safety

DoD officials ordered the “precautionary” removal of products containing DMAA from military retail stores and placed them on “‘medical hold’ pending further review of the product safety” after two soldiers who used supplements with the ingredient suffered heart attacks while training with their units, according to the Directorate of Strategic Communications, Office of the Surgeon General.

“The review will evaluate potential links between these adverse effects and the use of DMAA-containing products,” the directorate explains in a fact sheet.

“DoD leaders are concerned by the soldiers’ deaths in which DMAA was identified by toxicological testing. Other adverse events have been reported by military providers listing kidney and liver damage, seizures, loss of consciousness, heat injury and muscle breakdown during exertion and rapid heartbeat in service members who have used these products,” according to the Surgeon General’s unit.

USPlabs, the maker of two DMAA-containing products removed from military store shelves, disagrees with the military’s decision. The firm’s products remain available online and in other consumer retail sites, and the military’s action does not prohibit soldiers from buying the products from other outlets.

“There is absolutely no reason to remove DMAA-containing supplements from sale on certain military facilities. … To our knowledge, there is no scientific or medical research whatsoever stating DMAA-containing products are unsafe when used as directed,” the Dallas firm said in a Dec. 5 statement.

Duffy MacKay, the Council for Responsible Nutrition’s VP for scientific and regulatory affairs, added “the military is taking the high road” by suspending sales and investigating the ingredient’s safety. However, he said, “linking serious adverse events with a single agent is a difficult process.”

“If someone passes away and they had spaghetti that day and you find spaghetti in their system you can’t necessarily say spaghetti killed them. That is the case with all adverse event reports,” MacKay said.

The adverse event reports also must be placed in context, he added. “Hundreds of millions of doses of DMAA have been sold and there is a very insignificant number of adverse event reports.”

In the past, however, the content and not the quantity of adverse event reports has spurred FDA to request supplement product recalls.

In 2009, [Iovate Health Sciences Inc.] voluntarily recalled 14 Hydroxycut products at FDA’s behest after the agency investigated 23 reports of serious liver-related adverse events – including one death – dating back to 2002 Also see "Hydroxycut Recall Eyed As Trigger For Closer Look At Supplement AERs" - Pink Sheet, 18 May, 2009..

FDA Investigation Possible

The soldiers’ deaths and subsequent DoD action could trigger an FDA review of DMAA’s safety, efficacy and status as a dietary ingredient in the U.S.

An agency spokeswoman noted in a Jan. 5 email that “as a matter of policy, FDA does not comment on the safety, label or labeling, or claims made for products with parties other than the responsible firm during the course of any investigation for regulation action.”

She added, as with any complaint or concern the agency receives about products it regulates, FDA “will consider whether a violation of the Federal Food, Drug and Cosmetic Act has occurred and, if so, whether regulatory action is warranted in light of FDA’s enforcement priorities and resources.”

The supplement product categories in which DMAA most often is used – bodybuilding and weight-loss categories – are areas FDA watches closely for adulteration Also see "Supplement Industry Must Step Up As Adulteration Threat Grows – FDA" - Pink Sheet, 28 November, 2011..

Action Abroad Did Not Sway FDA

FDA declined to act against DMAA this summer when Health Canada classified it as a drug and pulled all products containing the ingredient from shelves.

Health Canada in July classified DMAA as a drug and medicinal ingredient, and found no DMAA products to date are authorized to market as a human or veterinary drug, an agency spokesman said.

The regulatory body determined DMAA was a drug “since DMAA possesses amphetamine-like activity by acting as a stimulant on the central nervous system.” It also found the ingredient cannot be classified as a natural health product because no scientific evidence shows it is a naturally occurring isolate from geranium, despite widespread claims made by firms.

CRN’s MacKay noted the absence of a response from FDA, which neither took action “nor announced an administrative action that would address the status of the ingredient.”

“FDA has not mentioned any safety issues about DMAA” to CRN, he said.

New Zealand acted on DMAA before Canada, moving in 2009 to restrict access to the drug, which at the time was a popular “party pill.” The associate minister of health accepted the advice of an expert advisory committee on drugs to prohibit the sale of DMAA to anyone younger than 18 years and sales of the products where alcohol is sold or from service stations or near where children gather.

The committee also recommended New Zealand ban advertising of DMAA and offering products containing the ingredient as a gift or reward, and instituted strict labeling and packaging requirements for DMAA-containing products.

The recommendation followed publicized adverse events linked to the ingredient, including severe headaches with vomiting and one cerebral hemorrhage. Another instance was documented in The New Zealand Medical Journal in December 2010. In that case a 21-year-old suffered a cerebral hemorrhage shortly after taking two capsules of DMAA with 150 mg of caffeine and one beer.

The “cerebral hemorrhage is likely to be linked to the ingestion of DMAA and caffeine. The time sequence is suggestive of cause and effect,” the article’s authors wrote.

Several class action lawsuits in the U.S. against the makers of DMAA-containing ingredients claim further adverse events.

Phil Harvey, chief scientific officer at Max Muscle, an Orange, Calif.-based retail chain with its own brand of supplements, said he is surprised FDA is waiting to enforce against DMAA given the recent deaths and foreign regulators’ previous actions.

“I don’t know what they are waiting for. … For deaths to occur is, to me, too late,” he said.

Now that “things are starting to blow up” it is “just a matter of time” until FDA bans the ingredient in supplements, Harvey predicts.

He explained the firm has never used DMAA in its Max Muscle Sports Nutrition branded products and “we are not planning to” despite tough competitive pressure in the sports nutrition category.

Legal Status Of DMAA Uncertain

Harvey added that he considered including DMAA in Max Muscle supplements, but “decided based on my research that it wasn’t legal, safe or efficacious for pre-workout.”

At the time of his review, he said only one Chinese study showed DMAA is a naturally occurring constitute of geranium oil, and he considered that study to be flawed.

The American Herbal Products Association also doubts the study linking DMAA to geranium oil. For example, a review of the chromatogram from the original paper, which appeared in the peer-reviewed Journal of Guizhou Institute of Technology in 1996, found an inadequate separation of compounds for mass spectrometer library matches, which is a reference tool.

Other concerns about “the experimental conditions, the interpretation of data, the quality of data reporting and the validation of findings” call into question whether the ingredient occurs naturally, AHPA said in August.

The trade group, like Harvey, determined “this reported finding of DMAA from geranium is not scientifically valid,” and there are no other known publically published reports indicating that DMAA is a natural product, according to an AHPA release.

Based on this discovery, AHPA decided its members will no longer be allowed to label DMAA as geranium oil or any part of the geranium plant, according to a trade requirement that goes into effect Jan. 13.

“The resultant policy is quite direct, essentially stating just that products that are not geranium should not be labeled as geranium,” AHPA President Michael McGuffin said in a Jan. 4 email.

“AHPA policy is also quite limited, and takes no position on the source of or legal status of the ingredient,” McGuffin added.

Harvey, however, believes DMAA is not a dietary supplement, but rather a synthetic drug.

He said DMAA “has more of a drug story than a dietary supplement story,” noting that Eli Lilly & Co. patented and synthesized DMAA as the nasal decongestant Forthane.

Is DMAA The Next Ephedra?

The current situation with DMAA “is playing out like a scenario that is very similar to ephedra,” which FDA banned from supplements in 2004, Harvey said Also see "FDA Regulatory Framework For Ephedra Ban Expected To Get Court Review" - Pink Sheet, 5 January, 2004..

DMAA “has the same story as ephedra … in terms of here is an ingredient for upper respiratory and now it is being used for weight loss” and bodybuilding, he explained.

Likewise, DMAA could be connected to the same adverse events as ephedra: heart attack, stroke, seizure and death.

Like ephedra, which is back on FDA’s radar screen as an adulterant, Harvey predicts massive recalls of DMAA products and a potential ban of the ingredient due to the adverse events Also see "Ephedra Back On Regulatory Radar As Supplement Adulterant" - Pink Sheet, 2 January, 2012..

Harvey alerted Max Muscle franchises about DoD’s investigation of DMAA. The U.S. military’s decision sends a strong message to retailers to voluntarily remove products with the ingredient, he said. Max Muscle stores can stock the products, which are legal in the U.S., but Harvey says very few do.

MacKay disagrees with Harvey’s assessment. “It is premature for companies to act on military activities … and to jump to conclusions about the safety of the ingredient until the data has been fully evaluated,” he said.

“The military could conclude, in fact, that the two events were not related to the products,” in which case the temporary ban would be lifted, he added.

More Research Needed

The scarcity of published research on DMAA is a substantial barrier to resolving the questions surrounding DMAA’s status and safety.

MacKay encourages firms that use DMAA in their products to publish research on the ingredient’s origin and safety to reassure regulators and ensure consumers use the products correctly.

One DMAA marketer, USPlabs in fact published what it claims are “ground breaking” studies on DMAA Dec. 8 on its website.

USPlabs claims safety studies of DMAA-containing OxyElite Pro found the product increased the heart rate an average of six beats per minute and a statistically significant but “mild and transient” increase in blood pressure, which the firm says is comparable to the effect seen in some studies after the administration of caffeine dosages equivalent to two to three cups of coffee. The studies did not find changes in liver and kidney function and found the supplement was well tolerated with no adverse events noted, the firm says.

A safety study of another DMAA product, Jack3d, found similar “small and transient changes in blood pressure” after two weeks of daily supplement consumption but no change in heart rate, USPlabs claims.

USPlabs expects to publish a fifth study in the near future assessing the safety of Jack3d after 10 weeks.

U.S. Military Investigates Supplement Ingredient DMAA, Bans Sales

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