Category: Nicotine

  • Synthetic Nicotine Regulation Clears House

    Synthetic Nicotine Regulation Clears House

    dc_slim

    The House of Representatives approved a $1.5 trillion spending package that would give the U.S. Food and Drug Administration authority to regulate synthetic nicotine. The bill now goes to the Senate.

    Synthetic nicotine—nicotine that is made in a lab rather than derived from tobacco—has long existed in a legal gray area, and many companies started using it after their natural nicotine products were denied market access by the FDA. Public health groups have been warning that synthetic nicotine e-cigarettes, such as Puff Bar, have grown in popularity among teens while skirting FDA oversight.

    The Food, Drug and Cosmetic Act, which includes the 2009 Tobacco Control Act, defines a tobacco product as “any product made or derived from tobacco that is intended for human consumption, including any component, part or accessory of a tobacco product (except for raw materials other than tobacco used in manufacturing a component, part or accessory of a tobacco product).”

    If the spending bill currently under consideration passes, the language of the Tobacco Control Act would change to define a tobacco product as “any product made or derived from tobacco, or containing nicotine from any source, that is intended for human consumption.”

    The synthetic nicotine provisions are set to take effect 30 days after the bill’s passage. Synthetic nicotine producers then have 60 days from its enactment—or 30 days after it becomes effective—to file premarket tobacco product applications with the FDA to legally stay on the market. Ninety days after the effective date, or 120 days after the bill’s passing, these manufacturers will have to stop selling their products if the FDA has not authorized them. At that point, the FDA can exercise its enforcement discretion.

    Anti-smoking activists welcomed the legislation. “By using synthetic nicotine, e-cig companies are avoiding public health protections for flavored tobacco products and still hooking teens,” tweeted billionaire philanthropist Michael Bloomberg. “With millions of kids still using e-cigs, we must get synthetic nicotine products off the market.”

    Consumer advocates, by contrast, warned the move would deny adult smokers access to lower risk alternatives. “Only the largest and most powerful vaping and tobacco companies can afford the lawyers and the time necessary to complete the paperwork necessary to pass the FDA’s process, meaning thousands of hard-working American business owners will now be forced to close, depriving millions of adult consumers of harm reducing options,” said Yael Ossowski, deputy director of the Consumer Choice Center.

    The FDA appears keen to crack down on synthetic nicotine. During his Senate confirmation hearing, FDA Commissioner Robert Califf vowed to close what he described as the synthetic nicotine “loophole.”

    Earlier, FDA Center for Tobacco Products Director Mitch Zeller indicated that the synthetic nicotine could be considered a component of e-cigarettes, which would have allowed the agency to assert authority over the substance under existing legislation.

  • FDA Likely to Regulate Synthetic Nicotine

    FDA Likely to Regulate Synthetic Nicotine

    Photo: Kristina Blokhin

    A bill intended to fund the U.S. government through September includes language that would give the Food and Drug Administration authority to regulate synthetic nicotine. The House of Representatives could vote on the legislation as early as today.

    Synthetic nicotine is currently not explicitly regulated by the FDA, and many companies started using it after their natural-nicotine products were denied market access by the agency. Public health groups have been warning that synthetic nicotine e-cigarettes such as Puff Bar have grown in popularity among teens while skirting FDA oversight.

    The Food, Drug & Cosmetic Act, which includes the 2009 Tobacco Control Act, defines a tobacco products as “any product made or derived from tobacco that is intended for human consumption, including any component, part, or accessory of a tobacco product (except for raw materials other than tobacco used in manufacturing a component, part, or accessory of a tobacco product).”

    If the spending bill currently under consideration passes, the language of the Tobacco Control Act would change to define a tobacco product as “any product made or derived from tobacco, or containing nicotine from any source, that is intended for human consumption.”

    The synthetic nicotine provisions would take effect 30 days after the bill’s passage. Synthetic nicotine producers would then have 60 days from its enactment—or 30 days after it becomes effective—to file premarket tobacco product applications with the FDA to legally stay on the market. Ninety days after the effective date, or 120 days after the bill’s passing, these manufacturers would have to stop selling their products if the FDA has not authorized them. At that point, the FDA could exercise its enforcement discretion.

    Consumer advocated have criticized the attempt to “sneak in” the synthetic nicotine provision into the spending bill.

    “The byzantine process of asking permission to sell harm reducing vaping products in the 21st century is asinine in itself,” said Yaël Ossowski, deputy director of the Consumer Choice Center. “But using sleight of hand during an emergency government funding bill to castigate millions of vapers and the entrepreneurs who make and sell the products they rely on is the definition of active harm.”

    “Only the largest and most powerful vaping and tobacco companies can afford the lawyers and the time necessary to complete the paperwork necessary to pass the FDA’s process, meaning thousands of hard-working American business owners will now be forced to close, depriving millions of adult consumers of harm reducing options.”

    The bill is purportedly backed by Juul Labs and Reynolds American, both of which face competition from Puff Bar and from e-liquid sold in vape shops and online.

  • 22nd Century to Launch VLN in South Korea

    22nd Century to Launch VLN in South Korea

    Photo: 22nd Century Group

    South Korea will be the first international market to commence sales of 22nd Century’s VLN reduced nicotine content cigarettes, the company announced in a press release.

    “South Korea is an ideal international launch market in many ways, with a high smoking rate among developed countries and a government strongly committed to smoking harm reduction. We expect the first sale of VLN reduced nicotine content cigarettes to our South Korean partner to occur by the end of March,” said 22nd Centur4y’s CEO, James A. Mish.

    “Approximately one in three adult men in South Korea are smokers, and an estimated 6 percent of adult women smoke. The government has worked over the past two decades to promote smoking cessation through a variety of means, including heightened tobacco prices, and remains committed to advancing alternative products to help curb smoking activity in the country. We are excited to make VLN reduced nicotine content products available in South Korea to help break the nicotine addiction cycle and support this important effort.”

    The company will continue its launch process in additional markets in Asia and Europe with limited regulatory barriers while also leveraging VLN’s modified-risk tobacco product (MRTP) authorization in the United States toward seeking approval in additional markets with higher regulatory barriers.

    In addition to its first international launch of VLN reduced nicotine content cigarettes in the more than $800 billion global tobacco market, 22nd Century Group is actively moving forward to launch VLN in the $80 billion U.S. market.

    The U.S. FDA authorized 22nd Century’s VLN reduced nicotine content cigarette products on Dec. 23, 2021. The company is currently executing its 90-day post-authorization plan to launch in its first U.S. pilot market.

  • Study: Nicotine Mandate Could Reduce Smoking

    Study: Nicotine Mandate Could Reduce Smoking

    Photo: Pcess609

    Requiring cigarette manufacturers to significantly reduce the nicotine content of their products could dramatically reduce smoking rates in New Zealand, reports Stuff, citing a new study published in The New Zealand Medical Journal.  

    In December, New Zealand unveiled an ambitious tobacco control plan that in addition to gradually raising the smoking age until it covers the entire population, includes a reduced nicotine mandate. New Zealand aims to reduce its smoking levels across to below 5 percent of the population by 2025.

    Mandating about 95 percent less nicotine in cigarettes could have a “plausible chance” of achieving the Government’s Smokefree 2025 goals, wrote Professor Nick Wilson and colleagues from the Department of Public Health at the University of Otago, Wellington.

    Wilson was relaxed about the anticipated uptick in vaping and illicit trade following such a mandate. Vaping is “substantially less harmful” than smoking and New Zealand’s remote location would offer some protection against cigarette smuggling, he noted.

    Assuming a full ban on nicotine was implemented on March 1, 2023, Wilson and his colleagues predicted the smoking initiation among 18–24-year-olds would reduce by 75 percent due to the nonaddictive nature of the denicotinised tobacco. That would translate into an annual reduction of about 6,500 smokers.

    Among older established smokers, the researchers assume that 33 percent would quit each year in 2023, 2024 and 2025.

    Such a “relatively high rate” of quitting could be sustained because low nicotine tobacco is not addictive and the “growing denormalisation of smoking,” according to the researchers.

  • Appropriate for the Protection of Health?

    Appropriate for the Protection of Health?

    Photo: 22nd Century Group

    The FDA’s focus on nicotine is coming at the expense of true harm reduction.

    Cheryl K. Olson

    I was gobsmacked last December when the U.S. Food and Drug Administration issued modified-risk tobacco product (MRTP) authorizations for two reduced-nicotine combustible cigarettes, 22nd Century Group’s VLN King and VLN Menthol King. Both contain non-GMO tobacco that’s very low in nicotine (VLN). If 22nd Century Group can reduce the disastrous health effects of smoking by offering low-nicotine combustible cigarettes, that’s great. What took me aback was the implicit message from the FDA on its priorities.

    VLN products such as these were supposed to be part of a smoking harm reduction landscape—one that includes approaches proven to reduce the risks of illness and death among cigarette smokers, such as vaping, heat-not-burn and smokeless tobacco. But this ideal, data-driven society in which addicted smokers bob gently down the famous continuum of risk via the path they prefer (perhaps starting with VLN cigarettes, perhaps with another product and ultimately landing at their low-risk nicotine maintenance or tobacco-free destiny) isn’t where we’re living.

    Such a Candide-like world would feature a rainbow of reduced-risk products that match the needs of individual smokers and smokers and people who influence them (such as doctors) fully aware of these products and of how and why they’re lower risk. They’d also know that traditional approaches to quitting (hello, “cold turkey” and nicotine-replacement therapy) have proved depressingly ineffective, especially among heavily addicted, low-income, longtime smokers: the folks who need our help the most.

    The FDA claimed to envision such an environment when Scott Gottlieb, then the agency’s commissioner, stated in 2017 that “Nicotine lives at the core of both the problem and, ultimately, the solution to the question of addiction and the harm caused by combustible forms of tobacco. … So, how can we take a new and comprehensive approach to nicotine?”

    Gottlieb continued, “Armed with the recognition of the risk continuum, and the reality that all roads lead back to cigarettes as the primary cause of the current problem, we need to envision a world where cigarettes lose their addictive potential through reduced nicotine levels. And a world where less harmful alternative forms, efficiently delivering satisfying levels of nicotine, are available for those adults who need or want them.”

    Instead, the FDA prioritized very low-nicotine cigarettes and dropped the ball on that last, essential part: the “less harmful alternative forms.” Those products, despite considerable and growing scientific evidence of their real-world effectiveness, have been left in limbo.

    A Passing Grade on the Wrong Test

    What exactly happened? An MRTP is simply a request to the FDA that a tobacco-related company be allowed to make some specified changes in how it describes a product or set of products to the general public through its packaging, marketing, advertising and other forms of promotion and communication.

    In this case, 22nd Century Group wanted to state that each of its products contains “95 percent less nicotine,” “helps reduce your nicotine consumption” and “VLN smells, burns and tastes like a conventional cigarette but greatly reduces your nicotine consumption.” They provided the scientific evidence to back up those claims.

    Among the hurdles for a successful MRTP authorization is that the manufacturer demonstrates that the product is “appropriate for the protection of the public health,” or APPH. In other words, that the requested modifications do or have the potential to do more good than harm if approved. That’s a core question that needs to be addressed in any tobacco-related application or authorization request to the FDA.

    The Tobacco Control Act of 2009 begins with the words, “To protect the public health ….” That shows the clear focus and intent of the legislation. While the phrase “appropriate for the protection of the public health” appears several times in the act, it’s frustratingly vague and subject to interpretation.

    What’s clear, however, is that the FDA should prioritize those aspects of smoking that are the most harmful to individual and public health. While reducing nicotine intake is appropriate for the protection of the public health, it should be nowhere near the top of the list.

    It’s Not the Nicotine That Kills

    Morbidity and mortality among smokers, including cancers and heart disease, are caused by the “tars” and other byproducts of combustion—what researchers often call harmful and potentially harmful constituents (HPHC). Because it’s addictive, nicotine is also considered an HPHC. As Michael Russell famously put it, “People smoke for the nicotine, but they die from the tar.”1

    In its February 2020 presentation on its products to an FDA Tobacco Products Scientific Advisory Committee panel, 22nd Century Group clearly states, “VLN cigarettes yield essentially the same HPHCs as conventional cigarettes. The benefits of VLN accrue from reduced cigarettes per day and reduced abuse liability.” That’s consistent with their authorization request since they’re only claiming a reduction in the amount of nicotine.

    Think about that for a moment. The premise that reduced nicotine in combustible cigarettes will reduce harm is based on an assumption that the number of cigarettes smoked will decrease. That’s because the other HPHCs—the substances that lead to illness and death—are the same in the very low-nicotine and the regular cigarettes. Will they?

    Compensatory Smoking

    Maybe. Maybe not. It’s an empirical question that requires research with these specific products. Researchers studying smokers who switched to earlier generations of low tar and low nicotine cigarettes, known as low-yield cigarettes, found that many engaged in what’s known as compensatory smoking.

    According to the Centers for Disease Control, “Most people who smoke are addicted to nicotine. They may compensate when smoking low-yield cigarettes in order to take in more nicotine.”5

    A historical review of tobacco industry approaches to marketing low-yield cigarettes concluded, “Unfortunately for the industry, smokers did not care much for the taste of reduced tar cigarettes and, as expected, the lower nicotine levels became a problem as well. Smokers were not receiving the same nicotine ‘satisfaction’ and therefore began to compensate for the reduction in nicotine by smoking more cigarettes, thus increasing their health risk.”2

    These earlier studies were conducted on combustible cigarettes with significantly higher levels of nicotine than the VLN products. Some well-respected smoking harm reduction experts such as Clive Bates theorize that the nicotine levels in this generation of cigarettes is so low that compensatory smoking will not be a problem. But how, then, is this different from the low success cold turkey approach? Also, what about dual use? There is nothing to prevent a smoker from using both types of products.

    What’s the Real Harm?

    But this distracts from the fundamental problem. The FDA’s focus is on the wrong chemical: nicotine. It’s often the first or only chemical most people can name when describing tobacco. That’s one of the reasons why the addictive quality of nicotine is so often conflated with combustible tobacco’s relationship with heart disease and cancer.

    Several studies of physicians’ knowledge about the clinical effects of nicotine find misperceptions are frustratingly common. Roughly four out of five doctors surveyed incorrectly linked nicotine to cardiovascular disease (83.2 percent), chronic obstructive pulmonary disease (80.9 percent) and cancer (80.5 percent).9 They should know better.

    This distortion of the role of nicotine among smokers, and some of the people who counsel them when they try to quit or at least reduce their medical risk, can interfere with their motivation to use some of the proven pathways away from combusted tobacco.

    This focus on nicotine reduction and the misunderstanding of its risks may be precluding addicted smokers from switching to products that significantly reduce harm. According to Public Health England, “One assessment of the published data on emissions from cigarettes and e-cigarettes calculated the lifetime cancer risks. It concluded that the cancer potencies of e-cigarettes were largely under 0.5 percent of the risk of smoking. Comparative risks of cardiovascular disease and lung disease have not been quantified but are likely to be also substantially below the risks of smoking. Among e-cigarette users, two studies of biomarker data for acrolein, a potent respiratory irritant, found levels consistent with nonsmoking levels.”

    My frustration is that the FDA, through its priorities and recent actions, is inadvertently reinforcing misinformation that interferes with the goal of protecting the public health by focusing on nicotine reduction at the expense of true harm reduction.

    Last year, I interviewed former industry scientist Justine Shaw Jackson for another Tobacco Reporter column; she spoke of the need to give people nicotine “without all the nasties in the smoke.” That phrase stuck in my head, creating a mashup of her words and Russell’s insight: “It’s not the nicotine that kills—it’s the nasties in the smoke.” Let’s embroider that phrase on pillows and send one to every doctor and nurse in the world.                

    Cheryl K. Olson is a California-based public health researcher who specializes in behavioral health issues and consults on tobacco product behaviors. She spent 15 years on the faculty of Harvard Medical School.
  • 22nd Century to Launch VLN Cigarettes in U.S.

    22nd Century to Launch VLN Cigarettes in U.S.

    Photo: 22nd Century

    22nd Century Group plans to launch its VLN reduced-nicotine cigarettes in a major U.S. metropolitan market by March 2022. The debut will be followed by a nationwide launch.

    On Dec. 23, 2021, the U.S. Food and Drug Administration authorized 22nd Century Group’s VLN King and VLN Menthol King as the first reduced-nicotine content cigarettes under the agency’s modified-risk tobacco product designation. Scientific studies show the company’s VLN reduced-nicotine content cigarettes “help you smoke less.”  

    “The FDA’s MRTP authorization of VLN ushered in a new reality—a combustible cigarette carrying an authorized harm reduction claim supported by extensive scientific and clinical studies, most of which were funded by federal health agencies,” said James A. Mish, CEO of 22nd Century, in a statement.

    “VLN is the only reduced harm product of its kind, and we are confident based on the research that it can absolutely be successful on its own or in combination with other harm reduction products. With an estimated 1,300 deaths per day associated with U.S. smoking, our products that can help people smoke less offer a truly game-changing prospect for millions of American adults who currently smoke.”  

    During the pilot phase, 22nd Century Group will test and optimize its marketing mix. The pilot will help the company better understand how adult smokers will use this product prior to advancing to national distribution, providing an unmatched tool for helping adult smokers find an off-ramp from nicotine addiction.

    “22nd Century has secured a well-known national retail partner for VLN’s pilot market launch phase,” said Mish. “We intend to deploy and test a wide array of marketing materials aimed at adult smokers looking for ways to help them smoke less. These will include marketing at the point of sale, direct materials sent to self-identified adult smokers interested in VLN and online resources, such as our new product site at tryvln.com.”

    While 22nd Century owns or controls the intellectual property that makes VLN tobacco possible, the company has reiterated its willingness and expectation to license the technology to strategic partners.

  • Momentum Building in U.S. for Regulating Synthetic Nicotine

    Momentum Building in U.S. for Regulating Synthetic Nicotine

    Photo: Aliaksandr Barouski

    Momentum appears to be building for the regulation of synthetic nicotine in the United States.

    On Dec. 15, U.S. Representative Mikie Sherrill introduced a bill designed to give the U.S. Food and Drug Administration the authority to regulate synthetic nicotine products just as it regulates nicotine products made or derived from tobacco.

    “This bill will ensure all tobacco products, including products made with synthetic nicotine, are regulated by the FDA in order to protect kids in our communities and those who may seek to use these products,” Sherrill said in a statement.

    The Federal Food, Drug and Cosmetic Act (FDCA) currently defines “tobacco product” as “any product made or derived from tobacco that is intended for human consumption, including any component, part or accessory of a tobacco product.”

    In November, FDA Center for Tobacco Products Director Mitch Zeller suggested synthetic nicotine could be considered a component of e-cigarettes, which would allow the agency to regulate it.

    The FDA could also seek to regulate synthetic nicotine as a drug. The FDCA defines drugs, among other things, as “articles (other than food) intended to affect the structure or any function of the body.”

    In the 1990s, the FDA tried to regulate nicotine as a drug and cigarettes and smokeless tobacco as “drug delivery devices.” In FDA v. Brown & Williamson Tobacco Corp., the U.S. Supreme Court found that the FDA lacked such authority.

    The 2009 Family Smoking Prevention and Tobacco Control Act gave the FDA the authority to regulate tobacco products. Should the FDA regulate synthetic nicotine as a drug today, it could point to recent legislation from Congress giving the FDA a role in this space more broadly. So far, however, the FDA has not taken this approach.

    Following a flurry of marketing denial orders in which the FDA forced many products containing tobacco-derived nicotine off the market, several manufacturers have switched to synthetic nicotine to avoid the agency’s rigorous and costly premarket review process.

    In response to such moves, lawmakers have initiated investigations and called for regulation of the category. On Nov. 16, nine senators sent a letter to the FDA imploring the agency to regulate synthetic nicotine products. The authors expressed concerns that e-cigarette manufacturers like Puff Bar are switching to synthetic nicotine to skirt FDA oversight and premarket review requirements to continue selling their products—including flavored products—that they assert appeal to youth.

    That same day, the North Carolina attorney general launched an investigation into Puff Bar. On Nov. 8, he sent letters to e-cigarette manufacturers Puff Bar and Next Generation Labs requesting extensive records pertaining to the production and marketing of the companies’ synthetic nicotine products.

  • FDA Nominee Vows to Close Synthetic Nicotine Loophole

    FDA Nominee Vows to Close Synthetic Nicotine Loophole

    Robert Califf

    Robert Califf vowed to close the synthetic nicotine loophole if appointed commissioner of the U.S. Food and Drug Administration, according to a report by Vaping360.

    During Califf’s nomination hearing on Dec. 14, Wisconsin Senator Tammy Baldwin expressed concern over reports that companies are switching to making flavored synthetic nicotine products in the wake of FDA marketing denial orders.

    “As FDA commissioner, how would you work to address the rise in youth use of synthetic nicotine, and will you commit to working with Congress to ensure that the FDA has the authorities and resources it needs to crack down on these products?” Baldwin asked.

    In response, Califf first noted that is crucial to appoint the right person to succeed Center for Products Director Mitch Zeller, who plans to retire in April 2022.

    “Secondly,” Califf continued, “this is not limited to children. I may have some family members using synthetic nicotine, I learned as I was going through the paces here. And what people don’t realize is that there are two enantiomers of nicotine—one of which is not occurring in nature—that are in this product, and its properties are not known.

    “So we’ve got to close this loophole,” Califf added, “so that we make sure that we understand the risks and benefits, and particularly deal with the issues in children.”

    The Senate Health, Education, Labor & Pensions Committee will vote soon on whether to recommend Califf’s nomination to the full Senate. If the committee approves him, the former commissioner can expect full Senate confirmation to be the new commissioner soon, probably in January.

  • 22nd Century Ready to Support Kiwi Plan

    22nd Century Ready to Support Kiwi Plan

    22nd Century Group announced today that it is ready to provide commercial support to the New Zealand Ministry of Health’s Smokefree Aotearoa 2025 Action Plan, including supplying reduced nicotine content combustible cigarettes able to meet New Zealand’s proposed standards.

    The final version of the plan introduced on Dec. 9 details comprehensive measures to reduce smoking, including legislation to implement a reduced nicotine mandate.

    “We applaud the bold plans in New Zealand, which is now leading the world in introducing novel and highly effective tobacco control strategies to end cigarette addiction,” said James A. Mish, chief executive officer of 22nd Century Group, in a statement.

    “This is an ambitious plan, and reduced nicotine content cigarettes such as our VLN products will be critical to its success. We are fully prepared to support New Zealand and its Smokefree Plan as it blazes a trail for other health agencies around the world to follow, including the United States FDA and the World Health Organization,”

    New Zealand’s plan details six key focus areas, the fourth of which is: “Making it easier to quit and harder to become addicted by only having low-level nicotine smoked tobacco products for sale and restricting product design features that increase their appeal and addictiveness.”

    With just 0.5 mg of nicotine per gram of tobacco, 22nd Century’s VLN reduced nicotine content cigarettes contain 95 percent less nicotine than conventional cigarettes, but they taste, smell and smoke the same, according to 22nd Century Group.

    22nd Century’s modified-risk tobacco product application is currently in the final stage with the U.S. Food and Drug Administration, and the company says it remains highly confident of a positive outcome given its recent dialogue with the agency.

  • Acting Unnaturally

    Acting Unnaturally

    Photo: artefacti

    Synthetic versus tobacco-derived nicotine

    Cheryl K. Olson and Willie McKinney

    Every year, the National Youth Tobacco Survey gathers data from U.S. middle school and high school students about all sorts of nicotine products and how they’re used. In 2021, for the first time the most popular brand of e-cigarette among underage users was a synthetic nicotine vape. Puff Bar was named “usual brand” by 26.1 percent of underage vapers, equaling the sum of the next three most popular brands: Vuse (10.8 percent), Smok (9.6 percent) and Juul (5.7 percent). While the summary of these latest findings in Morbidity and Mortality Weekly Report didn’t mention the word “synthetic,” the U.S. Food and Drug Administration certainly took note.

    One reason the FDA pricked up its ears is that synthetic nicotine, also known as nontobacco nicotine, lives in a legal gray area. The Family Smoking Prevention and Tobacco Control Act of 2009 expanded the FDA’s authority to regulate products “made or derived from tobacco” and created its Center for Tobacco Products.

    This begs the question of whether the FDA has regulatory authority over synthetic nicotine. Predictably, manufacturers who use it in ENDS products claim that the FDA does not have that authority. If that’s true, those manufacturers can bypass the lengthy and expensive premarket tobacco product application process and go directly to market. But there are others, including attorneys who’ve studied this law, who believe that even if synthetic nicotine is technically not covered by the 2009 Tobacco Control Act, it meets the definition of a drug and is therefore subject to FDA regulation.

    The substitution of synthetic nicotine for tobacco-derived nicotine has profound implications both for manufacturers and distributors of reduced-harm nicotine products. Is it a smart workaround, a temporary shelter or a costly dead end? Here are some of the key issues as well as ways to limit your risk as a company.

    The Options

    Over the past few months, many makers of flavored e-cigarette products have received marketing denial orders (MDOs) or fear receiving one. An MDO gives that manufacturer a limited number of choices: reapply for approval, get out of the business or sue the FDA for redress—or search for what it hopes is a legal loophole to the FDA’s regulatory authority. Hence, the move to synthetic nicotine as a too clever by half solution that carries with it underlying scientific, economic, legal and ethical issues.

    Let’s start with an economic issue, which may trump all the others. Synthetic nicotine is expensive. In fact, it’s up to 10 times the cost of tobacco-derived nicotine, according to Kevin Burd, CEO of North America Nicotine. One reason is that tobacco-derived nicotine is made from leftover scraps from processing tobacco leaves—often literally the stuff left on the factory floor. Synthetic nicotine, most of which is manufactured in China, is created through a variety of proprietary chemical processes.

    “As volumes increase, I can’t see the price of chemicals used in synthetic coming down to the price of waste tobacco, including dust,” said Burd. “It’s highly unlikely ever to be competitive.”

    Both synthetic nicotine and tobacco-derived nicotine occur in two structural forms (enantiomers) known as R-nicotine and S-nicotine. More than 99 percent of the nicotine in tobacco is S-nicotine. In synthetic nicotine, that balance can be 50-50.

    “Little is known about the pharmacological and metabolic effects of R-nicotine in humans,” says a 2021 article on the rise of synthetic nicotine  in Tobacco Control (Jordt SE. Synthetic nicotine has arrived. Tobacco Control 2021. doi: 10.1136/tobaccocontrol-2021-056626). In other words, synthetic product users could be unwitting research subjects. There are inexpensive tests for distinguishing between R- and S- forms of the chemical and ways of separating the R-isomer from the S-isomer. By comparison, telling the difference between synthetic S-nicotine and tobacco-derived S-nicotine can be quite costly.

    This leads to an interesting paradox. We don’t know how much of the supposed synthetic nicotine is actually tobacco-derived nicotine. There’s a financial incentive for a manufacturer simply to replace the more expensive version with the cheaper chemical and mislabel it. In fact, on its website, Next Generation Labs warns prospective customers, “There are several companies from China claiming to have synthetic nicotine. NGL has tested several of these products and discovered they are made or derived from tobacco.”

    Burd adds, “Quite likely, many [products that claim to be synthetic] are not really synthetic.”

    Some companies are weighing the cost of regulatory compliance versus the higher manufacturing cost of using synthetic nicotine. That’s a false choice, for it underestimates the costs of unknown safety risks, product testing and emerging regulations. Simply marketing a new synthetic nicotine product without providing the necessary scientific and behavioral research data to the FDA will, at the very least, generate a warning letter.

    Remember that the key reason for generating research data on a new product is to explore whether it will harm people. The FDA uses the term APPH (appropriate for the protection of public health). Not doing so puts your business at risk not only from regulatory actions but from civil litigation if someone gets hurt.

    A regulatory update by FDA Center for Tobacco Products Director Mitch Zeller at an Oct. 27 Food and Drug Law Institute conference addressed the challenge posed by synthetic nicotine. Zeller’s slide deck makes clear his belief that e-liquids that do not contain tobacco-derived substances “may still be components or parts of tobacco products and, therefore, subject to FDA’s tobacco control authorities.” It also states that the FDA is “in discussions with Congress about a potential legislative fix.”

    Advertisement

    The Wild West

    Burd expressed concern that synthetic nicotine, and the regulatory uncertainty driving its use, have put the vaping industry “back to the Wild West.” Even the pure S synthetic may contain residues from the unknown solvents that some new manufacturers use. Burd recommends that manufacturers who use synthetic nicotine “test their incoming material (emphasizing impurities and solvents), audit the supplier, do a toxicology review for product safety and be sure to use S-nicotine only.”

    That type of analysis is impractical for end users, of course.

    Finally, there’s the issue of whether a company is a “bad actor” that focuses on short-term financial profits at the expense of both public health and the lives of their customers. The FDA runs the risk of encouraging such unethical behaviors if it broadly bans products from those companies making sincere efforts to reduce the harm done to smokers of combustible cigarettes while ignoring companies that look for legal loopholes.

    A Marketing Throwback?

    The issue of synthetic nicotine regulation is likely to be resolved fairly soon. One reason is that the attractiveness of e-cigarettes to youth is rightfully a major concern of the FDA. Marketing materials for synthetic nicotine products have the tone of advertising done by an earlier iteration of Big Tobacco when it claimed that paper filters, toasting and other irrelevant variables reduced cigarettes’ negative health effects.

    • American Tobacco Company (1930): “20,679 physicians say Luckies are less irritating. Toasting removes dangerous irritants.”
    • Liggett & Myers (1931): “Chesterfield Cigarettes are just as pure as the water you drink.”
    • Brown and Williamson (1949): “Viceroys filter the smoke. As your dentist, I’d recommend Viceroys.”
    • Puff Bar (2021): “Our nicotine products are crafted from a patented manufacturing process, not from tobacco. The result? A virtually tasteless, odorless nicotine without the residual impurities of tobacco-derived nicotine.”
    • Next Generation Labs (2021): “TFN Nicotine is not derived from tobacco leaf, stem, reconstituted sheet, expanded or postproduction waste dust. The nicotine is made using a patented manufacturing process that begins with a natural starter material and progressively builds around the molecules of that material to create a pure synthetic nicotine.”

    These claims (from company websites) about differences between synthetic and tobacco-derived nicotine misleadingly hint at safety without providing real data. They skirt the important scientific issues and focus on emotionally resonant phrases like “begins with a natural starter material,” “without the residual impurities” and “create a pure synthetic nicotine.”

    Adolescents in particular may make the false inferential leap that synthetic nicotine somehow carries less risk or is less addictive than tobacco-derived nicotine, according to new research from Rutgers University and the National Institutes of Health. This, in turn, may lead nonsmoking, nonvaping teens to use the products often enough to become addicted. The risk of any new product to children is a tried-and-true political plank, so it’s likely to gain the attention of members of Congress, who could pass a law declaring all forms of nicotine to be under the purview of the FDA. —WMK and CKO

    Willie McKinney is the founder of McKinney Regulatory Science Advisors. He’s held senior regulatory roles at major tobacco product companies and served for three years as the industry representative on the FDA’s Tobacco Products Scientific Advisory Committee.
    Cheryl K. Olson is a California-based public health researcher who specializes in behavioral health issues and consults on tobacco product behaviors. She spent 15 years on the faculty of Harvard Medical School.