Nicotine Analogs Pose Possible Health Risks Yet Evade Regulation

Vape Additives that Mimic Nicotine Are Potent—and Largely Unregulated

By Bradley van Paridon

A modified version of nicotine, the addictive ingredient in cigarettes, appeared in the U.S. vaping market in May 2023, prompting alarm among tobacco researchers. These products are being marketed as beyond the reach of the U.S. Food and Drug Administration. According to health researchers, this is the latest in a long history of moves by tobacco companies to avoid regulation and amounts to a large-scale human safety experiment.

The company Charlie’s Holdings, Inc. launched the new line of vaping products called Spree Bar which contain Metatine, a trademarked name for its synthetic nicotine analog, 6-methylnicotine. Because of the narrow definition of nicotine in U.S. law, the addition of one chemical structure called a methyl group allows the company to market Metatine as indistinguishable from traditional vaping products’ nicotine while also avoiding any regulatory scrutiny. Other companies are doing the same with similar nicotine analogs in vaping liquids and oral pouches.

“As I see it, this is just the latest chapter in the industry’s very long and nefarious history of evading or trying to evade laws that were enacted and intended to protect the health and well-being of not only adults but children in the United States,” says Lauren Kass Lempert, a public health researcher at the Center for Tobacco Control Research and Education at the University of California, San Francisco.

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Charlie’s Holdings, Inc. did not respond to a request for comment.

The manufacture and distribution of e-cigarettes came under Food and Drug Administration jurisdiction in 2016 when they were deemed tobacco products and therefore subject to the Family Smoking Prevention and Tobacco Control Act. This law prohibits e-cigarette manufacturers from marketing their products without first obtaining FDA authorization, which requires an assessment of the risks they pose to young people. Studies show that flavors and coolants such as menthol are attractive to younger users, leading more of them to use these products.

U.S. law defines tobacco products as those “made or derived from tobacco, or containing nicotine from any source.” Nicotine is defined as “the chemical substance named 3-(1-Methyl-2-pyrrolidinyl) pyridine or [C₁₀H₁₄N₂], including any salt or complex of nicotine.” To get FDA authorization, Lempert says, “a company has to demonstrate with rigorous scientific evidence that the product is appropriate for the protection of the public health.” But Metatine, with its modified chemical structure, is not considered nicotineand isthereforeexempt from the marketing authorization requirement necessary to sell tobacco products in the U.S. In an e-mailed statement, an FDA spokesperson said that the agency was aware of nicotine analogs in the market and that while more research is required, it is also aware of data that shows that these analogs may be more potent than nicotine. According to the e-mail, the FDA is looking at the issue from “an agency wide perspective” and funding several research efforts on the topic.

According to Sairam Jabba, a tobacco regulatory scientist at Duke University, 6-methylnicotine may not legally be nicotine, but it may share the worrying health profile that prompted tobacco regulations to begin with. As far back as the 1970s, tobacco companies researched nicotine analogs such as 6-methylnicotine to try to find for molecules that might be more desirable for users and avoid future regulations. Jabba combed through these data, along with studies conducted in the 1990s at Duke that investigated nicotine receptor function, and found evidence that 6-methylnicotine is, in fact, a more potent molecule than nicotine.

Test after test in rodents showed that smaller doses of 6-methylnicotine elicited greater responses than nicotine for several outcomes, Jabba and his colleagues found. (In situations where human toxicology tests aren’t ethical, rodent models are used instead.) In rodents, the lethal dose for 6-methylnicotine is smaller than for nicotine. Studies also showed that less 6-methylnicotine was required to increase blood pressure and behavioral responses triggered by nicotine receptor activation. The analog even bound more strongly to nicotine receptors than nicotine itself and was more toxic to airway cells. Systematic studies on the addictive properties of 6-methylnicotine have not been done, and the findings may not fully translate to humans. But given that both molecules are used in a similar way in vaping products and the pharmacological targets are the same, Jabba says, “you would expect the outcomes to be very similar.”

For Hanno Erythropel, a chemist at Yale University, who performed an analysis of Spree Bar products with Jabba, the unknowns surrounding nicotine analogs are worrying. Of the nine Spree Bar products tested, all had a discrepancy between actual and labeled amounts of 6-methylnicotine present, with the actual amount being much lower than stated. While this may seem reassuring, it could indicate intentional or accidental mislabeling because less of the potent ingredient is needed to produce the same effects as nicotine. The researchers also studied eight products with no labeled 6-methylnicotine from another company and found that six of them still contained small amounts of 6-methylnicotine.

“Now you’re using a product that you don’t really know the effect of, and you don’t know how much is there,” Erythropel says. Given the potential increased potency of 6-methylnicotine, mistaken or intentional mislabeling scenarios are both concerning. It is also unclear how the analogs react when they are burned, mixed in a vaping fluid or metabolized by the body—all important and unanswered safety questions, Erythropel says.

Lempert believes this is a clear-cut case for authorities to follow the precautionary principle and act before these products get a greater foothold in the market. Some countries—and recently California state law—use a broader definition of nicotine that includes some of these analogs, but amending U.S. national law is a lengthy process. Lempert says that other regulatory bodies, such as the Consumer Product Safety Commission, could help fill the gap. “They can issue and enforce mandatory standards for consumer products,” she explains, “or in the event that standards wouldn’t adequately protect the public, they can ban hazardous consumer products.”