6-Methylnicotine
6-Methylnicotine is a nicotine analogue in which a methyl group is added at the 6-position of the pyridine ring. It has been identified in certain electronic cigarettes and oral pouch products marketed as nicotine alternatives, sometimes under the trade names Metatine and Nixodine-S. Studies in cells, animal models, and early human biomonitoring indicate higher activity at nicotinic acetylcholine receptors and differences in toxicity and metabolism compared with nicotine.
Although sometimes marketed as "not made or derived from tobacco", a 2025 analytical study reported trace natural occurrence of 6-MN in tobacco at a mean of 0.32 micrograms per gram and detected low-μg/mL levels in some previously analysed high-nicotine e-liquids, complicating origin-based regulatory claims.
History
Reports of nicotine analogues date to the early 1960s. In 1963, Erdtman, Haglid and Wellings described synthetic analogues of nicotine, establishing early approaches to ring- and side-chain modification of the alkaloid.In 1967, Haglid demonstrated that treatment of nicotine with methyllithium furnished multiple methylnicotine isomers, including 6-methylnicotine; the study detailed conditions and product distributions.
Industry-affiliated work expanded these routes in the early 1980s. A 1981 communication showed that methylmagnesium bromide addition to nicotine N-oxide provided both 2- and 6-methylnicotine, and that methyllithium could favor 2-substitution under certain conditions. A 1983 full paper from the Philip Morris U.S.A. Research Center mapped reaction pathways and racemization behaviour for organometallic methylations of nicotine and nicotine N-oxide, reporting formation of 2-, 4- and 6-methylnicotines under varied conditions.
Through the 1990s, academic structure–activity studies reported higher receptor affinity and/or functional potency for several 6-substituted nicotine analogues compared with nicotine in rodent and membrane assays.
In late 2023, U.S. disposable e-cigarettes delivering 6-methylnicotine appeared under the trademark "Metatine", advertised as "PMTA-exempt". Subsequent analyses in 2024–2025 described additional U.S. products, identification of 6-methylnicotine in Australia, and oral pouches in Europe, as well as a 2025 report of trace natural occurrence of 6-methylnicotine in cured tobacco and several tobacco products.
Chemistry
6-MN is the methyl homologue of nicotine with substitution at the 6-position of the pyridine ring. The enantiomer is the biologically more active form at central α4β2 nicotinic acetylcholine receptors, analogous to -nicotine.Pharmacology
Rodent and in-vitro binding studies indicate that methyl substitution at the 6-position can increase affinity and functional potency at nAChRs compared with nicotine. Analyses of U.S. products in 2024 reported commercial liquids labelled as containing 6-MN used the -enantiomer exclusively. A 2025 metabolism study in mice and in human urine after product use identified multiple 6-MN metabolites and a shift toward N-oxidation relative to nicotine.Toxicology
Cell and animal studies report greater cytotoxicity or distinct toxic effects for 6-MN compared with nicotine. In human bronchial epithelial cells, 6-MN-containing e-liquids generated more reactive oxygen species in aerosols and induced higher cytotoxicity across tested doses. An earlier in-vitro study likewise found higher cytotoxicity and broader transcriptomic disruption for 6-MN relative to nicotine in BEAS-2B cells. In vivo, mice exposed to 6-MN exhibited acute neurotoxic signs not observed with an equimolar dose of nicotine within the same study framework.Occurrence
A 2025 analytical survey reported average levels of 0.32 μg/g 6-MN in cured tobacco and several tobacco products; re-analysis of archived chromatograms from nine high-nicotine e-liquids showed 6-MN at a mean 6.3 ± 1.4 μg/mL.Presence in consumer products
Commercial branding associated with 6-methylnicotine has included Metatine, Nixodine-S, and Imotine. Independent analyses of nicotine-analogue flavoured e-liquids, sold under various names, reported undeclared 6-methylnicotine alongside under-labelled nicotinamide, which has no known nicotinic receptor agonist activity, raising concerns about product transparency.In 2023–2024, U.S. disposable e-cigarettes marketed with 6-MN were analysed by academic laboratories. Across nine flavours labelled "5% 6-MN", measured concentrations were approximately 0.58–0.63% ; neotame and WS-23 were also detected. Outside the United States, 6-MN has been identified in some e-liquids sold in Australia in 2024 and in oral pouches marketed in Europe as "tobacco- and nicotine-free", with some products containing up to 20 mg 6-MN per pouch.