Nicotine analogues may pose health risks but escape regulation

Nicotine-mimicking e-cigarette additives are powerful but largely unregulated

Bradley Van Paridon

In May 2023, a modified version of nicotine, the addictive ingredient in cigarettes, appeared on the U.S. e-cigarette market, raising alarm among tobacco researchers. These products are being sold outside the jurisdiction of the U.S. Food and Drug Administration. Health researchers say this is the latest in a long line of attempts by tobacco companies to evade regulation, amounting to large-scale human safety experiments.

Charlie’s Holdings has launched a new line of e-cigarette products called Spree Bars that contain Methatine, a trade name for 6-methylnicotine, a synthetic nicotine analogue. Because nicotine is narrowly defined under U.S. law, the addition of an additional chemical structure called a methyl group allows the company to market Methatine as indistinguishable from the nicotine in traditional e-cigarette products and avoid regulatory scrutiny. Other companies have done the same thing, using similar nicotine analogues in e-liquids and oral pouches.

“In my view, this is just the latest chapter in a very long and nefarious history of the tobacco industry evading or attempting to evade laws that are designed to protect the health and well-being of adults and children in the United States,” said Lauren Cass Lempert, a public health researcher at the University of California, San Francisco’s Center for Tobacco Control Research and Education.

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

The manufacture and distribution of e-cigarettes came under the jurisdiction of the Food and Drug Administration in 2016, when they were considered tobacco products and covered by the Family Smoking Prevention and Tobacco Control Act. This law prohibits e-cigarette manufacturers from selling their products without FDA approval, which requires an evaluation of the risks to youth. Research has shown that flavors and cooling agents such as menthol are attractive to youth users, making them more likely to use these products.

Under U.S. law, tobacco products are defined as “products made from or derived from tobacco, or that contain nicotine from any source.” Nicotine is “3-(1-methyl-2-pyrrolidinyl)pyridine or (C₁₀H₁₄no₂), including salts or complexes of nicotine. To gain FDA approval, “companies must demonstrate with rigorous scientific evidence that their products are suitable for the protection of public health,” Lempert said. However, methatine, which has an altered chemical structure, is not considered nicotine and is therefore exempt from the marketing authorization requirements necessary to sell tobacco products in the United States. In an emailed statement, an FDA spokesperson said the agency is aware that there are nicotine analogues on the market and that while more research is needed, it is also aware of data indicating that these analogues may be more potent than nicotine. According to the email, the FDA is looking at the issue from an “agency-wide perspective” and is funding several research efforts on the subject.

According to Duke University tobacco control scientist Sairam Java, 6-methylnicotine may not be legally nicotine, but it may share the worrying health profile that sparked tobacco control in the first place. As far back as the 1970s, tobacco companies have researched nicotine analogues, such as 6-methylnicotine, to find a molecule that is more desirable to users and avoid future regulation. Java reviewed these data, as well as research conducted at Duke in the 1990s that explored the function of nicotine receptors, and found evidence that 6-methylnicotine is in fact a more potent molecule than nicotine.

In multiple tests in rodents, Java and his colleagues showed that low doses of 6-methylnicotine elicited greater responses in some outcomes than nicotine. (When toxicity tests on humans are ethically unacceptable, rodent models are used instead.) In rodents, 6-methylnicotine was less lethal than nicotine. The study also showed that 6-methylnicotine was less effective at increasing blood pressure and enhancing behavioral responses caused by nicotine receptor activation. The analog bound more strongly to nicotine receptors and was more toxic to airway cells than nicotine itself. No systematic studies have been done on the addictive potential of 6-methylnicotine, so the findings may not be entirely applicable to humans. But given that both molecules are used in the same way in e-cigarette products and have the same pharmacological targets, “we would expect the results to be very similar,” Java says.

For Yale University chemist Hanno Erythropel, who analyzed Spreever products with Java, the unknowns surrounding the nicotine analogues are worrying. In all nine Spreever products tested, there was a discrepancy between the actual amount of 6-methylnicotine and the amount listed on the label, with the actual amount being much less than what was listed. While this may be reassuring, it could indicate intentional or accidental mislabeling, since it takes a smaller amount of the active ingredient to achieve the same effect as nicotine. The researchers also looked at eight other brands that didn’t list 6-methylnicotine on the label and found that six of them still contained small amounts of 6-methylnicotine.

“Right now you’re using a product that you don’t actually know what it’s doing, and you don’t know what it’s doing,” Erythropel says. Because 6-methylnicotine’s potency is potentially increasing, both false and intentional mislabeling scenarios are of concern. It’s also unclear how similar substances react when burned, mixed into e-cigarette liquid, or metabolized in the body. These are all important unanswered safety questions, Erythropel says.

Lempert believes this is a clear case for authorities to follow the precautionary principle and act before these products become established on the market. Some countries, and most recently California law, use broader definitions of nicotine that include some of these similar substances, but it will take a long time to revise national U.S. laws. Lempert says other regulatory agencies, such as the Consumer Product Safety Commission, could help fill this gap. “They can issue and enforce mandatory standards for consumer products,” she explains. “Or they can ban dangerous consumer products if the standards don’t adequately protect the public.”