With recent warning letters, ingredients’ regulatory status takes center stage, expert says

By Hank Schultz contact

- Last updated on GMT

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Getty Images
The recent slew of warning letters on DMHA and phenibut signals a new scrutiny on the part of FDA of ingredient status without reference to other issues, says an attorney with a long history in the field.

Claudia Lewis, who heads the FDA practice at the law firm Venable, said the recent issuance of the letters marks a new era in the agency’s scrutiny of the status of dietary supplement ingredients.  Prior to her time at Venable, Lewis did a stint with the prominent firm Emord & Associates.

Sole focus on regulatory status of ingredients

The 11 letters, eight of which focused on DMHA and three on phenibut, were unique in that they focused solely on whether these ingredients qualified as legal dietary ingredients.  The letters had nothing to say about company operations, such as whether illegal disease claims were being made or if the companies had GMP failure.

“This is the first  time in my experience where the agency is not raising all of these ancillary issues,” Lewis said. “It does signal that the agency is evaluating whether you qualify as a dietary ingredient.”

DMHA, or dimethylhexamine, is a stimulant ingredient that goes by many names. Those mentioned in the warning letters include 2-aminoisoheptane, 1,5-DMHA, 2-amino-6-methylheptane, 1,5-Dimethylhexylamine, 2-Isooctyl amine, and Octodrine. 

DMHA was one of the ingredients in a long line that formulators turned to after ephedra was banned.  This rogues gallery includes others such as DMAA and BMPEA.  DMHA was originally developed as a nasal decongestant in the 1950s.

FDA noted in the warning letters that DMHA does not tick off any of the boxes for being a legal dietary ingredient.  There is no evidence that it was on the market prior to the DSHEA grandfather date of Oct. 15, 1994.  Failing that, there is no NDI notification on file for the ingredient.  And the agency said it does not appear that any company or individual has compiled a GRAS dossier on the ingredient, whether self affirmed or one that has been submitted to the agency.

The other ingredients, phenibut, also goes by many names, including 4-amino-3-phenylbutyric acid HCl, fenibut, phenigam, PhGaba, phenigamma, phenygam, 4-Amino-3-phenylbutanoic acid, β-(Aminomethyl)benzenepropanoic acid, beta-(Aminomethyl)hydrocinnamic acid, and β-phenyl-γ-aminobutyric acid.  This stimulant was reportedly developed in the Soviet Union in the 1960s and has been used to treat a number of conditions including anxiety. 

 It has never been approved for use as a drug in the US.  Nor, like DMHA, has it cleared any of the regulatory hurdles for being classified as a legal dietary ingredient.

Safety concerns spurred action

Safety questions about these ingredients had been raised in prominent scientific papers as well as by industry trade associations.  This is probably why FDA chose to act on these two ingredients in this manner, Lewis said.

“Safety is the first and last question that the agency usually asks,”​ Lewis said. “But in recent years the agency has been kind of silent with respect to the safety profiles of some new ingredients.”

It has been noted by industry critics, as well as by some at FDA itself, that the number of New Dietary Ingredient Notifications appears to be only a small subset of what’s new on the market.  In other words, some product developers seem to have been betting that FDA would take a long time to get around to vetting the status of their new ingredients as long as they didn’t wave a big ‘come and get me’ flag with over the top disease treatment claims and the like.

Lewis said the new warning letters signals that that free pass might have expired.

“I don’t know that if the trade associations had not signaled to the agency that these two ingredients were a bit of a problem that we would be where we are now.  But these letters do signal that the agency is willing to act on the letter of the law. Do you qualify as a dietary ingredient—yes or no?  If the answer is no, then there is no need to go into these other things,” ​she said.

Drug preclusion might not be a blanket ban

Lewis cautioned that FDA’s word is not gospel on these matters and some issues are open to interpretation.  The agency’s position in recent years on the legality as dietary ingredients of synthesized forms of molecules first identified in plants is one example. Another is whether having a drug form on the market before a supplement means a given molecule is for all time and in all forms forbidden for use in a dietary supplement.

“If you really don’t qualify as a dietary ingredient it’s a very hard argument to make about why your product should be on the market,” ​Lewis said.

“But the fact that it was first studied as a drug?  Is it actually the same ingredient, the same metabolite? Are you using it in the same amount as the drug, or for different indications? All of those questions might mean that it might no be precluded as a dietary ingredient,” ​Lewis said.

“The fact that a given molecule has been first studied as a drug means you are about 85% of the way to a no as to whether it can be a legal dietary ingredient.  But 85% is not 100%, and as a lawyer I would want to explore that 15% and see where it takes us,”​ she said.

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