Eight years ago, U.S. regulators cautioned 1,3-dimethylamylamine was an unlawful ingredient in dietary supplement products.

Several companies received warning letters in 2012 over the then-popular ingredient known simply as DMAA, which FDA described as an “amphetamine derivative” posing health risks that may lead to such cardiovascular problems as arrhythmias, heart attack or shortness of breath.

Todd Harrison, a lawyer in Washington, D.C., who advises clients on FDA regulations, agreed the vast majority of companies that receive warning letters from FDA try to address the agency’s concerns.

“I would say 90% of them do,” he said in an interview.

That 10%, though, may give regulators heartache. In the case of DMAA, the outliers included USPlabs, a now defunct sports nutrition company whose former executives have pleaded guilty to federal charges and are facing the likelihood of prison. USPlabs, which received a warning letter in April 2012, eventually destroyed millions of dollars in DMAA-containing products, OxyElite Pro and Jack3d, after they were administratively detained.

In 2013, FDA also seized DMAA-containing products from a company that hadn’t received a letter the previous year as part of the agency's batch of warnings: Hi-Tech Pharmaceuticals. Regulators wouldn’t find Hi-Tech and its owner, Jared Wheat, as accommodating as USPlabs. The Norcross, Georgia-based supplement manufacturer sued the government, triggering litigation that has coursed through the district and appellate courts for the last seven years.

In an April 8 decision, the U.S. Court of Appeals in Atlanta denied Hi-Tech’s request for a rehearing before the entire panel, virtually extinguishing Hi-Tech’s court challenges unless it requests, and is granted, review by the U.S. Supreme Court. Hi-Tech did not immediately respond to a request for comment on the ruling.

Last year, in a 2-to-1 decision, a three-judge panel of the 11th Circuit affirmed a 2017 district court summary judgment order, which held DMAA is not a dietary ingredient under the Dietary Supplement Health and Education Act of 1994 (DSHEA).

Even if Hi-Tech filed a petition for certiorari with the Supreme Court, it’s unlikely the justices would take the case. “Of the 7,000 to 8,000 cert petitions filed each term, the court grants certiorari and hears oral argument in only about 80,” according to the SCOTUSblog.

Bottom line: The fate of DMAA in supplements may finally be over after nearly a decade of legal wrangling. But the aftermath could be ugly for Hi-Tech and possibly others since class action lawyers likely smell blood.

“Here, we have not just FDA’s opinion, but a litigated judicial opinion that favors FDA regarding the ingredient, and now a denial of a rehearing on the issue,” said Rick Collins, a lawyer in Mineola, New York, and an expert on sports supplements, in an email. “Class action lawyers will be on the lookout for all brands that sold DMAA at some point in the not-too-distant past, seeking plaintiffs who bought the products mislabeled as dietary supplements.”

Added Collins, a partner with Collins Gann McCloskey & Barry PLLC: “Since settlements can be costly, brands seeking to bring novel dietary ingredients to market may be more likely to take a step back and double-check DSHEA compliance.”

Hi-Tech already faces at least one class action suit related to DMAA and two other ingredients flagged by FDA. Jack Wenik, an attorney in Newark, New Jersey, representing Hi-Tech, said the company denies the allegations and plans to “vigorously defend itself.” Abbas Kazerounian, one of the lawyers representing the named plaintiffs, declined to comment on the litigation pending in the U.S. District Court for the Central District of California.

The DMAA case isn’t merely about a sole ingredient or the mounting setbacks facing Hi-Tech and its owner, who along with his company was indicted in 2017 on unrelated criminal charges that remain pending. (Wheat denied any wrongdoing and called the charges “bogus” after he was arrested.)

‘Trace amounts’

That a federal appeals court in Atlanta weighed in on DMAA—and more broadly, food law—creates some precedent for the wider supplement industry. “People have to stop using trace levels found in ingredients as a basis of being able to market a dietary ingredient,” Harrison, a partner with Venable LLP, concluded. “I think that’s really the lesson from it.”

In the litigation against Hi-Tech, FDA claimed DMAA didn’t qualify as a dietary ingredient under DSHEA. Hi-Tech argued otherwise, contending the ingredient can be found in geranium plants.

The 11th Circuit sided with FDA, holding DMAA didn’t qualify as a botanical or constituent of one because DMAA was found in only “trace amounts.”

“The safest conclusion is this: it is unlikely that Congress used the term ‘constituent’ to mean a substance that is present in a plant in only trace amounts and that has never been derived from a plant for use in any medicinal, cosmetic or dietary product,” District Judge Robert Hinkle wrote in the 11th Circuit’s decision.

Ricardo Carvajal, an attorney in Washington, D.C., pointed out DSHEA doesn’t contain a requirement that a constituent of a plant be derived in quantities greater than “trace amounts.”

“You don’t find that limitation in the statute,” he said in an interview.

Synthetic botanicals

Carvajal, a former FDA lawyer, found most significant the 11th Circuit’s suggestion that a synthetic botanical could qualify as a dietary ingredient so long as the substance could be naturally found in the plant and in more than negligible or trace amounts.

The court’s finding stands in contrast to FDA’s position in 2016 draft guidance that “a synthetic copy of an herb or other botanical does not qualify as a dietary ingredient under section 201(ff)(1)(C) of the FD&C (Federal Food, Drug & Cosmetic) Act.” That’s the section of the law listing “an herb or other botanical” as among the dietary ingredients that meet the definition of a dietary supplement.

To complicate matters, however, FDA asserted in the guidance that a synthetic copy of a botanical could qualify as a dietary ingredient “if the synthetic copy has itself been used as a lawfully marketed ingredient in the conventional food supply.” The agency was referring to 201(ff)(1)(E) of the FD&C Act. This provision is what lawyers have described as the “catch-all” for meeting the definition of a dietary supplement, namely “a dietary substance for use by man to supplement the diet by increasing the total dietary intake.”

FDA’s 2016 opinion doesn’t sit well with James (Jim) Prochnow, a lawyer in Denver whose early career was spent defending President Richard Nixon and working as a trial attorney at the Justice Department.

“I’m a believer in looking at the plain language of the statute,” he said in an interview. “That statute says nothing about synthetics or common use by man.”

Fortunately, for companies that disagree with the agency, FDA’s document is a draft only and non-binding guidance. On the other hand, the 11th Circuit’s opinion also does not necessarily settle the question of whether synthetic botanicals meet the definition of an herb or other botanical.

“You could even look at this and say, ‘This is dicta,’ because ultimately the court seems to be concluding that this [DMAA] isn’t a botanical, so you don’t even have to go on to the next step,” Carvajal, a director of Hyman, Phelps & McNamara P.C., reasoned. “They seem to be saying, ‘Look, if it’s present in geraniums, it’s present in such tiny amounts that we don’t think it’s a botanical.' So if that’s true, then we don’t even get to the question of whether it’s OK for it to be a synthetic or not.”

What’s more, the 11th Circuit’s decision is not binding on other federal appellate courts, noted Prochnow, a shareholder with Greenberg Traurig LLP. He suggested other appellate courts faced with similar issues would consider the 11th Circuit’s decision, but it would be only one of myriad considerations.

Hi-Tech never concealed that its DMAA was synthetically manufactured. As a public health agency with limited resources, the argument goes, FDA is unlikely to target a synthetic botanical unless it also has safety concerns about the product.

GRAS analysis

That was the case with DMAA, and the question was whether the substance was GRAS (generally recognized as safe). The 11th Circuit cited conflicting testimony about whether the ingredient was safe or not.

The appeals court conceded the government would not have been entitled to summary judgment if the issue was whether DMAA was safe since “neither side’s evidence is conclusive.”

“But the issue is not whether DMAA is safe,” Hinkle wrote in the 11th Circuit’s decision. “[The] issue is only whether DMAA is generally recognized as safe. It plainly is not. On the issue of general recognition, the FDA was entitled to summary judgment.”

The 11th Circuit’s opinion, Harrison said, underscored that companies doing a GRAS self-affirmation should be confident that it would satisfy FDA if the agency reviewed the safety data.

“If I file this tomorrow with FDA, will they agree with you?” Harrison said, highlighting the question companies should be asking if they don’t plan to inform FDA of their GRAS determination through a voluntary submission. “If the answer is ‘no,’ then they need to go back to the … drawing board.”

An essential element of the GRAS standard, Prochnow said, is the general recognition of safety by qualified experts, as the 11th Circuit highlighted.

“And if the FDA can show that there is a significant debate or question about safety among the expert community, such that you can no longer claim a consensus, then you don’t have GRAS status,” Carvajal remarked. “It’s enough to just be able to prove to the court ‘there’s a real controversy here,’ and once FDA does that, the court doesn’t really have much choice but to take FDA’s side on it.”