Synthetic Nicotine Derivatives
Synthetic nicotine is a manufactured form of nicotine, produced in a laboratory, as opposed to being extracted from tobacco leaves. Synthetic nicotine (tobacco-free nicotine) is chemically identical to natural nicotine (tobacco-derived nicotine) but is made in a laboratory using synthetic processes.
Several synthetic derivatives of nicotine are being explored as safer, more potent, or less addictive alternatives to natural nicotine, with potential applications in research, smoking cessation, or other therapeutic contexts. However, more recently, research efforts have primarily focused on modifications to bypass the vaping and nicotine pouch regulations or enhance the user experience – even if many synthetic nicotine derivatives remain understudied in terms of long-term health impacts, and some studies have raised concerns about their safety and potency.
The most well-known nicotine derivatives are:
6-Methyl nicotine: A derivative formed by adding a methyl group at the sixth carbon position of the pyridine ring. This modification alters the structure of nicotine and may affect its pharmacological properties, such as how it interacts with nicotinic acetylcholine receptors in the brain and body. It is more potent and potentially more cytotoxic than nicotine, with limited safety data available. 6-Methyl nicotine is mainly used in e-cigarettes to bypass nicotine regulations in countries like Australia and the U.S.
Nicotine Salts: A combination of nicotine with organic acids like benzoic acid. It is popular in e-cigarettes because they deliver nicotine more smoothly to the user, allowing for higher concentrations without the harshness of freebase nicotine. Nicotine salts are a milder alternative to freebase nicotine but still lead to nicotine addiction.
Nornicotine: A derivative formed by demethylation of nicotine, where a methyl group is removed from the nitrogen atom. Nornicotine naturally occurs in tobacco plants but is also explored for its role in the metabolism of nicotine and its potential therapeutic uses. It is believed to contribute to nicotine addiction and has been studied for its interactions with nicotinic receptors. However, it is less potent than nicotine and might have a different safety profile.
Anatabine and Anabasine: These are minor tobacco alkaloids structurally related to nicotine. Both are being researched for their effects on nicotine receptors and potential health applications. Anatabine, for instance, has been studied for its anti-inflammatory properties and potential in treating neurodegenerative diseases like Alzheimer’s. These compounds are less addictive than nicotine but are still under evaluation for their long-term health effects.
Nicotine Analogs: Researchers are exploring a variety of nicotine analogs that interact with nicotinic acetylcholine receptors in different ways. These compounds are designed with a hopeful purpose to reduce cravings and withdrawal symptoms while avoiding nicotine’s addictive effects. Some analogs being tested include varenicline-like compounds (used in Chantix) that partially stimulate the nicotine receptors without delivering the same addictive effects.
Specifically, 6-methyl nicotine has gained attention as a nicotine alternative for its use to circumvent the strict regulations on nicotine vapes in the US and Australia. It is now at the center of regulatory discussions around synthetic nicotine compounds. The NJOY-owner, Altria highlighted the emerging use of 6-methyl nicotine in vapes and other smoking alternatives in the US as a new threat to the regulation of the tobacco industry; moreover, Altria urged U.S. Food and Drug Administration (FDA) to evaluate these compounds and establish authority over them. The Agency itself is also concerned, stating that nicotine alternatives used in vapes, such as 6-methyl nicotine, is potentially more potent and addictive than nicotine itself, though the scientific data remains incomplete.
In Australia, where nicotine is categorized as a controlled substance and its sale is tightly regulated, the Government is in a witch hunt against 6-methyl nicotine. In 2024, Australia restricted the sale of vapes to pharmacies only. Pharmacists are allowed to sell low strength vapes (up to 2% nicotine) to adults without a prescription. Adults seeking high strength vape (more than 2% nicotine) and under-18s need a prescription from a health practitioner to buy vapes from a pharmacy. Ahead of these restrictions becoming effective, vape manufacturers began introducing 6-methyl nicotine, which is technically not nicotine as defined by (then) existing laws and cannot be detected in routine nicotine testing. This loophole allowed its sale without the same regulatory oversight as nicotine, bypassing the above-mentioned restrictions. However, Australian authorities closed the regulatory loophole in mid-2024, effectively banning all vapes – whether they contain nicotine or alternatives like 6-methyl nicotine – from retail sales except in pharmacies.
More recently, it is reported that three large Chinese vape companies, Hangsen, Zinwi Biotech and Smoore, are researching nicotine-like chemicals (“nicotine analogs”) as a substitute for nicotine used in vapes although assessing the health implications of these substances may still need years of investigation1.
Recent Scientific Research
A newly published article2 in Toxicological Sciences highlights growing concerns over the use of nicotine analogs in e-cigarettes, particularly 6-methyl nicotine (6-MN) and nicotinamide, amid limited toxicological evidence and gaps in regulatory oversight. The article, published by researchers from the University of North Carolina at Chapel Hill, argues that products containing nicotine analogs are emerging faster than the scientific evidence needed to assess their health risks. The authors focus on products marketed as alternatives to nicotine and, in some cases, as products that fall outside existing tobacco-product regulations.
6-MN is the more significant concern from a pharmacological perspective. Also known as Metatine, it is a structural analog of nicotine that can activate nicotinic acetylcholine receptors. Earlier laboratory research has found that 6-MN can be more potent than nicotine at certain nicotinic receptors, while animal studies have indicated greater toxicity than nicotine at comparable measures. However, the available evidence remains limited, particularly regarding the effects of long-term inhalation in humans.
Recent research has added to those concerns. A 2025 study found that heating 6-MN in e-liquids generated reactive oxygen species and that exposure to 6-MN-containing aerosols produced oxidative and cellular effects in human bronchial epithelial cells. A separate 2026 study using a three-dimensional human respiratory tissue model found that nicotine and 6-MN aerosols produced distinct biological responses, further demonstrating that the two compounds cannot simply be assumed to have equivalent toxicological profiles.
The regulatory issue is particularly important because 6-MN has been used in products marketed as “PMTA-exempt” or nicotine-free. The emergence of these products followed the FDA’s extension of its tobacco-product authority to synthetic nicotine in 2022, creating incentives for manufacturers to explore structurally related compounds that are not explicitly identified as nicotine under existing statutory definitions. The authors argue that this represents a potential regulatory gap requiring attention.
Nicotinamide presents a different issue. It is a form of vitamin B3 and does not appear to act as a nicotine receptor agonist. Research has found no evidence that nicotinamide activates nicotinic acetylcholine receptors or is converted into nicotine. Nevertheless, products containing nicotinamide have been marketed as nicotine substitutes capable of providing effects similar to nicotine. Researchers have also documented products combining nicotinamide with 6-MN, raising additional questions about what consumers are actually inhaling.
The authors therefore argue that the regulatory framework needs to evolve alongside the market for nicotine substitutes. The central concern is not that the health risks of 6-MN or nicotinamide have already been conclusively established in humans, but that products containing pharmacologically active or poorly characterized compounds are reaching consumers without the level of toxicological evidence normally expected for new nicotine products. The issue could become increasingly important as manufacturers seek alternatives to conventional nicotine. A 2025 study found that small amounts of naturally occurring 6-MN are also present in tobacco and nicotine derived from tobacco, but the concentrations identified in conventional tobacco are far below those used intentionally in nicotine-substitute products. The emergence of 6-MN and nicotinamide therefore represents a new regulatory frontier for the nicotine industry: products may increasingly be designed around compounds that reproduce some characteristics of nicotine while falling outside traditional regulatory definitions.
References:
- https://www.reuters.com/business/healthcare-pharmaceuticals/top-chinese-vape-firms-research-nicotine-alternatives-2024-09-25 ↩︎
- Graham, A. A., & Corteselli, E. M. (2026). Nicotine analogs in e-cigarettes: Unrecognized health risks and insufficient regulatory oversight. Toxicological Sciences. Online publication ↩︎
