Recalls, Availability, and Content of Dietary Supplements Following FDA Warning Letters

Abstract

This study examines the frequency of product recalls and the presence of FDA-prohibited drugs in supplements after FDA warning letters.

Some dietary supplements are adulterated with novel and unapproved stimulants. These analogues of amphetamine, ephedrine, and other drugs have been linked to serious health risks, including hemorrhagic stroke and sudden death. The US Food and Drug Administration (FDA) is responsible for removing these hazardous supplements from the market, and the agency has attempted to do so by issuing warning letters to manufacturers (Supplement).^1,2,3

Whether FDA warning letters lead manufacturers to recall or reformulate products is unknown. We assessed the frequency of product recalls and the presence of FDA-prohibited drugs in supplements after FDA warning letters.

Methods

Dietary supplement products were included if they had previously been the subject of a warning letter from the FDA regarding the presence of the amphetamine analogue β-methylphenethylamine (BMPEA), the ephedrine analogue methylsynephrine, or the dimethylamylamine analogue octodrine (DMHA). The FDA issued warning letters for these stimulants in 2015, 2016, and 2019, respectively.^1,2,3 The warning letters mandate that manufacturers inform the FDA of the steps the firm will take to correct the violation and prevent similar violations in the future. The Google search engine, manufacturers’ websites, and the FDA’s website were searched for evidence of recalls of the implicated products. Products that remained available for sale using the Google search engine in January 2022 were purchased online. Powder from the dietary supplement products was reconstituted in methanol and analyzed for the presence and quantity of FDA-prohibited ingredients by liquid chromatography quadrupole time-of-flight mass spectrometry using a previously described method.⁴

Results

The FDA issued warning letters targeting the presence of BMPEA, methylsynephrine, or DMHA in 31 supplement products. Of these 31 products, 1 (3%) was recalled by the manufacturer. Nine of the 31 products (29%) remained available for purchase online a mean of 6 years after the FDA issued warning letters. Four of the 9 available products (44%) listed the presence of at least 1 prohibited ingredient on the label: 1 product label declared the same prohibited ingredient that prompted the FDA warning letter and 3 product labels declared other FDA-prohibited ingredients. After chemical analysis, 5 of the 9 products (56%) were found to contain at least 1 FDA-prohibited ingredient (Table). Four products contained 1 prohibited ingredient and 1 product contained 3 different prohibited ingredients. Two products contained the same prohibited ingredient for which the FDA issued the warning letter.

Table. Prohibited Ingredients in Products Sold After Receiving Warning Letters From the FDA.

Ingredient prompting FDA warning letter (date issued)	Label claim	FDA-prohibited ingredient(s) openly declared on label of products purchased after warning letter	Label-recommended serving size	Label maximum daily servings	FDA-prohibited ingredients found by chemical analysis to be present in products purchased after warning letter	Measured quantity of ingredient per serving size determined by chemical analysis, mean (SD), mg	Measured quantity of ingredient in maximum recommended daily servings determined by chemical analysis, mg
BMPEA (4/23/15)	Diet aid for energy and weight loss	Methylsynephrinea	1 capsule	4	Methylsynephrinea	50.1 (0.3)	200.4
BMPEA (4/23/15)	Diet aid for energy and weight loss	Methylsynephrinea	1 capsule	4	Methylsynephrinea	39.9 (0.04)	159.6
		2-aminoisoheptaneb			Octodrine (1,5-DMHA)c	78.3 (0.1)	313.2
					1,4-DMAAd,e	0.7 (0.01)	2.8
Methylsynephrine (3/31/16)	Extreme fat burner		1 capsule	4	Methylsynephrinea,e	42.5 (0.08)	170
DMHA (4/10/19)	Rapid weight loss	Noopeptf	1 capsule	2	Omberacetam (Noopept)f	28.3 (0.6)	56.6
DMHA (4/10/19)	Workout intensifier	2-aminoisoheptaneb,g	1 scoop	1	Octodrine (1,5-DMHA)c	145.5 (0.9)	145.5

Abbreviations: 1,4-DMAA, 1,4-dimethylamylamine; 1,5-DMHA, 1,5-dimethylhexylamine; BMPEA, β-methylphenylethylamine; FDA, US Food and Drug Administration.

^a Methylsynephrine is an ephedrine analogue that has never been approved for use in the US. In countries in which it has been used as a pharmaceutical, the drug has been formulated in 16-mg, 20-mg, 32-mg, and 40-mg doses.

^b 2-Aminoisoheptane is a nonspecific chemical term that manufacturers use to refer to octodrine (1,5-DMHA).

^c Octodrine was developed as an inhaled bronchodilator but has never been approved for oral use in the US. In Germany, the drug has been marketed as part of a multicomponent oral medication containing 8.2 mg, 16.5 mg, or 33 mg of octodrine.

^d 1,4-DMAA is an analogue of 1,3-dimethylamylamine, the latter of which was introduced in the US in the 1940s as a nasal inhaler to compete with the amphetamine nasal inhalers on the market at the time. To our knowledge, 1,4-DMAA has never been approved as a medication for use in the US or elsewhere; therefore, pharmaceutical doses are not available.

^e Ingredients not declared on label.

^f Omberacetam was developed in Russia, where it is marketed as Noopept. The mechanism of action is unknown. Omberactam has never been approved for use in the US. In Russia, the typical pharmaceutical dose is 10 mg.

^g Product openly lists the same prohibited ingredient that prompted the initial FDA warning letter.

Discussion

After issuance of FDA warning letters targeting specific supplement products, 29% remained available for purchase, with most containing a prohibited ingredient. The FDA has several enforcement tools to remove hazardous ingredients from dietary supplements, including issuing warning letters to manufacturers, requesting or mandating that manufacturers recall products, and publishing public notices. Previous research found that after FDA-announced voluntary recalls of dietary supplements, 10% of these supplements were still available for sale and 67% were adulterated with prohibited drugs.⁵ Another study analyzed supplements purchased after FDA public notifications; 75% of products contained prohibited adulterants years after the FDA announced public notices.⁶

This study has limitations, including that the sample size was small and that only 1 sample of each supplement was analyzed. Given these limitations, it is not known whether the results are generalizable to all dietary supplements subject to FDA warning letters or whether the presence of adulterants might vary from batch to batch or over time. The methodology also did not permit determining the fate of the products that were not recalled or available—they may have been discontinued or rebranded following the FDA warning letters.

This study raises questions regarding the FDA’s actions to ensure that manufacturers are compliant with the agency’s warning letters. The FDA should consider ways to ensure that prohibited drugs are removed from supplements, perhaps by testing products sold after warning letters and mandating recalls whenever products remain adulterated.

Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.

Supplement.

FDA Warning Letter