Nicotine analogues pose potential health risks but are not regulated

Nicotine-imitating vape additives are powerful and largely unregulated

TO Bradley van Paridon

A modified version of nicotine, an addictive ingredient in cigarettes, hit the U.S. vaping market in May 2023, raising alarm among tobacco researchers. The products are marketed as being outside the reach of the U.S. Food and Drug Administration. Health researchers say it’s the latest in a long history of moves by tobacco companies to skirt regulation and represents a massive experiment in human safety.

Charlie's Holdings, Inc. has launched a new line of vaping products called Spree Bar that contain Metatine, the trademarked name for a synthetic nicotine analogue, 6-methylnicotine. Because of the narrow definition of nicotine in U.S. law, the addition of a single chemical structure, called a methyl group, allows the company to market Metatine as indistinguishable from the nicotine in traditional vaping products, and to avoid any regulatory scrutiny. Other companies are doing the same with similar nicotine analogues in e-liquids and oral pouches.

“In my view, this is just the latest chapter in a very long and sordid history of an industry that is trying to circumvent or evade laws that are designed to protect the health and well-being of not only adults but also children in the United States,” says Lauren Cass 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 production and distribution of e-cigarettes came under the jurisdiction of the Food and Drug Administration in 2016, when they were deemed tobacco products and therefore subject to Law on the Prevention of Smoking in the Family and the Fight against Tobacco Smoking. The law prohibits e-cigarette makers from selling their products without first receiving FDA approval, which requires an assessment of the risks they pose to young people. Research shows that flavors and cooling agents like menthol are attractive to young users, prompting more of them to use the products.

U.S. law defines tobacco products as those “made or obtained from tobacco or containing nicotine from any source.” Nicotine is defined as “a chemical called 3-(1-methyl-2-pyrrolidinyl)pyridine or [C₁₀H₁₄N₂]“including any salt or complex of nicotine.” To get FDA approval, Lempert says, “a company must demonstrate through rigorous scientific evidence that the product is suitable to protect the public health.” But Methatin, with its altered chemical structure, is not considered nicotine and is therefore exempt from the marketing authorization requirement needed to sell tobacco products in the U.S. In an emailed statement, an FDA spokesperson said the agency is aware of nicotine analogs on the market and that while more research is needed, it is also aware of data that shows these analogs may be more potent than nicotine. The FDA is looking at the issue from a “broad agency perspective,” according to the email, and is funding several studies on the topic.

6-methylnicotine may not be legally nicotine, but it may share the alarming health profile that prompted tobacco regulation in the first place, said Sairam Jabba, a tobacco regulation expert at Duke University. As early as the 1970s, tobacco companies were researching nicotine analogs like 6-methylnicotine to try to find molecules that might be more desirable to users and avoid future regulations. Jabba looked at that data, as well as research from the 1990s at Duke that looked at nicotine receptor function, and found evidence that 6-methylnicotine is actually a more powerful molecule than nicotine..

Test after test in rodents showed that lower doses of 6-methylnicotine produced more pronounced responses than nicotine in several outcomes, Jabba and his colleagues found. (In situations where human toxicology tests are unethical, rodent models are used instead.) In rodents, the lethal dose of 6-methylnicotine is lower than that of nicotine. The studies also showed that less 6-methylnicotine was needed to produce the blood pressure increases and behavioral responses caused by nicotinic receptor activation. The analog even bound more strongly to nicotinic receptors than nicotine itself, and was more toxic to airway cells. Systematic studies of 6-methylnicotine’s addictive properties have not been conducted, and the findings may not fully translate to humans. But given that both molecules are used in similar ways in vaping products and the pharmacological targets are the same, Jabba says, “one would expect the results to be very similar.”

For Hanno Erythropel, a Yale University chemist who analyzed the Spree Bar products with Jabba, the unknowns surrounding the nicotine analogs are troubling. Of the nine Spree Bar products tested, all had a discrepancy between actual and labeled amount of 6-methylnicotine presenthowever, the actual amount is much lower than stated. While this may seem reassuring, it may indicate intentional or accidental mislabeling, since it takes less of the potent ingredient to produce the same effects as nicotine. The researchers also looked at eight products from another company that did not label 6-methylnicotine 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 of it is in there,” Erythropel says. Given the potentially increased potency of 6-methylnicotine, both scenarios of mislabeling or intentional mislabeling are concerning. It’s also unclear how the analogs react when they’re burned, mixed with vaping liquid, or metabolized in the body — all important and unresolved safety questions, Erythropel says.

Lempert believes this is a clear case for authorities to follow the precautionary principle and act before these products gain much traction in the marketplace. 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 long process. Lempert says other regulators, 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 if the standards fail to adequately protect the public, they can ban dangerous consumer products.”