The group, which consisted of Cohen, of the Harvard Medical School, John Travis, PhD of NSF, an expert from the US Department of Defense and two Dutch researchers, published their findings Wednesday in the journal Clinical Toxicology. The researchers bought products being marketed as dietary supplements from online outlets. Of the six products, two were marketed for weight loss whereas the other four were categorized as pre workout products. After analysis, the products were found to contain the following ingredients: 2-amino-6-methylheptane (also known as octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA).
Family tree of dodgy ingredients
DMAA has been ruled by FDA to be an illegal dietary ingredient since 2013, when it was taken off the market because of safety concerns. But it still continues to show up at the fringes of the dietary supplement industry. The lone high profile holdout was Hi Tech Pharmaceuticals, which had openly sold products containing the ingredient while a legal wrangle with FDA ran its course. Hi Tech founder Jared Wheat reportedly agreed in early October to stop selling products containing the ingredient as part of a bail deal associated his recent indictment on money laundering and mail fraud charges. Wheat was among the promoters of the ingredient who claimed to have evidence that DMAA is a constituent of geranium, something that FDA has disputed.
DMBA has been in FDA’s crosshairs almost as long as DMAA. Purported to be a constituent of dendrobium, an orchid species, DMBA is not a legal dietary ingredient because FDA has ruled that it is a New Dietary Ingredient for which no notification is on file.
In both cases, these ingredients were initially brought to market purporting to be botanical extracts, something which experts disputed. Nevertheless, that marketing strategy appears to be aimed at what promoters see as a weakness in the regulatory structure, namely that a pre-DSHEA positioning affords an easier path to market.
Octodrine is another case entirely. The paper says this substance was once briefly marketed as a drug in the US in the early 1940s, and was mentioned in the 1947 edition of the Physicians Desk Reference, a compilation of manufacturers’ prescribing information on drugs. The drug was used in a nasal spray to treat bronchitis symptoms. The study also mentions that the drug was an ingredient in oral preparations in Germany and elsewhere up to the mid 2000s in formulas marketed to treat hypotension, asthma and other conditions. While octodrine is clearly an Active Pharmaceutical Ingredient (API), there have been allegations that it is a naturally occurring substance. Some references—none of which have been confirmed, the researchers said—link it to one of several species of botanicals and even to fish or shellfish.
Finding the next new thing
One of the paper’s coauthors, John Travis, PhD, senior research scientist for NSF, said the group had been on the lookout for what might replace DMAA in the market.
“We were on the lookout for the next new ingredient would be. We were hoping to catch it just as it entered the marketplace and, with octodrine, it looks like we did,” Travis told NutraIngredients-USA.
“The really troubling thing is that these people are using ingredients for which there is no real safety information. For drugs back in the 1940s, they didn’t do safety trials like we do today. And we found octodrine at three times the levels of the 1940s drug. It’s important to note that these products were freely for sale. We didn’t have to go somewhere on the ‘dark Web’ to find them,” he said.
Flip sides of the coin
Amy Eichner, PhD, the special adviser on drugs and supplements for the United States Anti Doping Agency, said she applauds the researchers’ efforts to shine a light on a troubling issue.
“It’s both a happy and a sad day. Studies like this are great because it shows that various groups of scientists and clinicians are aware of this problem and they think it’s important enough to study. But it’s a sad day for athletes, members of the military and general consumers because marketers continue to flood the market with products that contain active pharmaceuticals,” she said.
Duffy MacKay, senior vice president of the Council for Responsible Nutrition, said Cohen et al. identified something that no one in the responsible industry can condone. While it is painful to see these issues continue to plague the market, MacKay said it’s necessary to keep shining a light on these practices.
“As much as Dr Cohen has been an adversary of the industry you have to respect his intent here. He’s trying to point out dangerous behavior by outliers in our industry. As much as we have as an industry spent time trying to point out that these are really outliers, this is still our problem. We need to continue to support any effort to protect consumers,” he said.
Chink in the regulatory armor
To some degree, MacKay agreed with the notion that underhanded players like these have found a niche in which they can operate, one created by the regulatory structure as it stands. Ingredients that look more and act more like pharmaceuticals but fly the wispiest of botanical flags are difficult to deal with within the present regulatory and enforcement structure. Perhaps it’s time regulations evolved to keep step with the times, though MacKay said he wasn’t sure what a new structure might look like.
“I don’t think it’s going to be acceptable in the next 20 years to have ingredients showing up on the market in this way. The current regulatory structure is not appropriate for ingredients like this. Our structure is intended for foods and food ingredients. When DSHEA was written, when the GMPs were written, the structure was more appropriate,” he said.
“Then again, if you were to go to these companies and ask to see their GMP records—these guys aren’t following any rules anyway,” MacKay said.
Corrine Newhart, a spokewoman for FDA, said the agency will add the information in Cohen’s paper to the growing literature on the subject of stimulant-like ingredients.
“In general, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health,” she said.
“Firms can often lawfully introduce dietary supplements to the market without even notifying FDA; however, pre-market notification is required when a dietary supplement contains a new dietary ingredient. To date, we have never received a new dietary ingredient notification for a product containing 1,3-DMAA, 1,4-DMAA, 1,3-DMBA, DMHA, or octodrine, the compounds highlighted in the Cohen study,” Newhart said.
Dan Fabricant, PhD, president and executive director of the Natural Products Association, said finding stimulants of this kind is not terribly surprising, and he disputed the notion that these products are ‘flooding’ the market.
“The position of the agency has been very clear on DMAA and this is nothing new. The fact that it is still out there is troubling, but people make this out to be a bigger concern than it is,” he said.
Source: Clinical Toxicology
“Four experimental stimulants found in sports and weight loss supplements: 2-amino-6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA)”
Published online 8. November 2017
Authors: Cohen P, et al.