6-Methylnicotine

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6-Methylnicotine
6-Methylnicotine.svg
Names
IUPAC name
2-Methyl-5-[(2S)-1-methylpyrrolidin-2-yl]pyridine
Other names
6-MN
Identifiers
3D model (JSmol)
ChemSpider
EC Number
  • (S) enantiomer:899-314-6
PubChem CID
UNII
  • (S) enantiomer:InChI=1S/C11H16N2/c1-9-5-6-10(8-12-9)11-4-3-7-13(11)2/h5-6,8,11H,3-4,7H2,1-2H3/t11-/m0/s1
    Key: SWNIAVIKMKSDBJ-NSHDSACASA-N
  • racemic:CC1=NC=C(C=C1)2CCCN2C
  • (S) enantiomer:CC1=NC=C(C=C1)[C@@H]2CCCN2C
Properties
C11H16N2
Molar mass 176.263 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

6-Methylnicotine (6-MN) 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 (in disposables) and Nixodine-S (sold as a benzoate salt or free base). [1] [2] 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. [3] [4]

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 (μg/g) and detected low-μg/mL levels in some previously analysed high-nicotine e-liquids, complicating origin-based regulatory claims. [5]

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. [6]

In 1967, Haglid demonstrated that treatment of nicotine with methyllithium furnished multiple methylnicotine isomers, including 6-methylnicotine; the study detailed conditions and product distributions. [7]

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. [8] A 1983 full paper from the Philip Morris U.S.A. Research Center (Richmond, Virginia) 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. [9]

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. [10] [11]

In late 2023, U.S. disposable e-cigarettes delivering 6-methylnicotine appeared under the trademark "Metatine", advertised as "PMTA-exempt". [12] Subsequent analyses in 2024–2025 described additional U.S. products, [2] identification of 6-methylnicotine in Australia, [13] and oral pouches in Europe, [14] as well as a 2025 report of trace natural occurrence of 6-methylnicotine in cured tobacco and several tobacco products. [5]

Chemistry

6-MN is the methyl homologue of nicotine with substitution at the 6-position of the pyridine ring. The (S) enantiomer is the biologically more active form at central α4β2 nicotinic acetylcholine receptors, analogous to (S)-nicotine. [2]

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. [15] Analyses of U.S. products in 2024 reported commercial liquids labelled as containing 6-MN used the (S)-enantiomer exclusively. [2] A 2025 metabolism study in mice and in human urine after product use identified multiple 6-MN metabolites (e.g., 6-methylcotinine, 6-methyl-3′-hydroxycotinine) and a shift toward N-oxidation relative to nicotine. [4]

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 (ROS) in aerosols and induced higher cytotoxicity across tested doses. [16] An earlier in-vitro study likewise found higher cytotoxicity and broader transcriptomic disruption for 6-MN relative to nicotine in BEAS-2B cells. [17] In vivo, mice exposed to 6-MN exhibited acute neurotoxic signs not observed with an equimolar dose of nicotine within the same study framework. [4]

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 (purchased 2018–2022) showed 6-MN at a mean 6.3 ± 1.4 μg/mL. [5]

Presence in consumer products

Commercial branding associated with 6-methylnicotine has included Metatine (disposable e-cigarettes in the United States), Nixodine-S (supplier listing), and Imotine (described as a benzoate salt by ingredient suppliers). [18] [19] 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. [2]

In 2023–2024, U.S. disposable e-cigarettes marketed with 6-MN (as "Metatine") were analysed by academic laboratories. Across nine flavours labelled "5% 6-MN", measured concentrations were approximately 0.58–0.63% (87–88% lower than labelled); neotame (sweetener) and WS-23 (coolant) were also detected. [2] Outside the United States, 6-MN has been identified in some e-liquids sold in Australia in 2024 [13] and in oral pouches marketed in Europe as "tobacco- and nicotine-free", with some products containing up to 20 mg 6-MN per pouch. [14]

Regulation

In the United States, a 2022 statutory update brought products "containing nicotine from any source" under FDA tobacco authority; chemical analogues such as 6-MN are not explicitly named, and federal agencies have noted potency concerns while reviewing available data. [18] [1] In the Netherlands, the National Institute for Public Health and the Environment (RIVM) derived advisory emission values for nicotine and 6-MN in non-tobacco products (0.028 mg nicotine and 0.0030 mg 6-MN per product at the lowest recommended level). [20] In Australia, the Therapeutic Goods Administration (TGA) initiated consultation in 2025 on creating a Schedule 7 (Dangerous Poison) entry for 6-methylnicotine. [21]

See also

References

  1. 1 2 Rumney, Emma (29 May 2024). "Nicotine-like chemicals in U.S. vapes may be more potent than nicotine, FDA says". Reuters. Retrieved 8 September 2025.
  2. 1 2 3 4 5 6 Erythropel, H. C.; Jabba, S. V.; Silinski, P.; Anastas, P. T.; Krishnan-Sarin, S.; Zimmerman, J. B.; Jordt, S. E. (7 August 2024). "Variability in Constituents of E-Cigarette Products Containing Nicotine Analogues". JAMA. 332 (9): 753–755. doi:10.1001/jama.2024.12408. PMC   11307159 . PMID   39110443.
  3. ↑ "Some E-Cigarette Chemicals Mimic Nicotine, Possibly Bypassing Regulation". Duke Health. 7 August 2024. Retrieved 8 September 2025.
  4. 1 2 3 Xie, Z.; Conklin, D. J.; Jin, L. (21 July 2025). "Characterizing oxidative metabolites of 6-methylnicotine (6MN; aka Metatine): divergent metabolism from nicotine and identification of urinary biomarkers of exposure". Toxicological Sciences. 207 (2) kfaf107. doi:10.1093/toxsci/kfaf107. PMC  12469198. PMID   40690396.
  5. 1 2 3 Pankow, J. F.; Luo, W.; McWhirter, K. J.; Sengupta, M.; Strongin, R. M. (23 May 2025). "Levels of the nicotine analog 6-methyl nicotine as a naturally formed tobacco alkaloid in tobacco and tobacco products". Scientific Reports. 15 (1) 17945. Bibcode:2025NatSR..1517945P. doi:10.1038/s41598-025-01392-6. PMC   12102161 . PMID   40410306.
  6. ↑ Erdtman, H.; Haglid, F.; Wellings, I.; von Euler, U. S. (1963). "Synthetic analogues of nicotine. I." (PDF). Acta Chemica Scandinavica. 17: 1717–1726. doi:10.3891/acta.chem.scand.17-1717 . Retrieved 13 September 2025.
  7. ↑ Haglid, F. (1967). "The methylation of nicotine with methyl-lithium". Acta Chemica Scandinavica. 21 (2): 329–334. doi:10.3891/acta.chem.scand.21-0329. PMID   6048663.
  8. ↑ Secor, H. V.; Chavdarian, C. G.; Seeman, J. I. (1981). "The radical and organometallic methylation of nicotine and nicotine N-oxide". Tetrahedron Letters. 22 (33): 3151–3154. doi:10.1016/S0040-4039(01)81850-5.
  9. ↑ Seeman, J. I.; Secor, H. V.; Howe, C. R.; Chavdarian, C. G.; Morgan, L. W. (1983). "Organometallic methylation of nicotine and nicotine N-oxide: reaction pathways and racemization mechanisms". Journal of Organic Chemistry. 48 (25): 4899–4904. doi:10.1021/jo00173a023.
  10. ↑ Dukat, M.; Dowd, M.; Damaj, I. M. (1999). "Synthesis, receptor binding and QSAR studies on 6-substituted nicotine derivatives as cholinergic ligands". European Journal of Medicinal Chemistry. 34 (1): 31–40. doi:10.1016/S0223-5234(99)80038-5.
  11. ↑ Wang, D. X.; Booth, H.; Lerner-Marmarosh, N.; Abood, L. G. (1998). "Structure–activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency" . Drug Development Research. 45 (1): 10–16. doi:10.1002/(SICI)1098-2299(199809)45:1<10::AID-DDR2>3.0.CO;2-G.
  12. ↑ Jordt, S. E. (22 November 2023). "An electronic cigarette pod system delivering 6-methyl nicotine, a synthetic nicotine analog, marketed in the United States as "PMTA exempt"". medRxiv (Preprint). doi:10.1101/2023.11.21.23298778. PMC   10690343 . PMID   38045384 . Retrieved 13 September 2025.
  13. 1 2 Jenkins, C.; Kelso, C.; Morgan, J. (27 August 2024). "6-Methylnicotine: a new nicotine alternative identified in e-cigarette liquids sold in Australia". Medical Journal of Australia. 221 (6): 333–335. doi: 10.5694/mja2.52423 . PMID   39188177.
  14. 1 2 Vanhee, C.; Dill, M.; Canfyn, M.; Tuenter, E.; Barhdadi, S. (2024). "The emergence of a novel synthetic nicotine analog 6-methyl nicotine (6-MN) in proclaimed tobacco- and nicotine-free pouches available in Europe" . Drug Testing and Analysis. 17 (8): 1368–1379. doi:10.1002/dta.3841. PMID   39697046.
  15. ↑ Dukat, M.; Fiedler, W.; Dumas, D.; Damaj, I. M.; Martin, B. R.; Rosecrans, J. A.; James, J. R.; Glennon, R. A. (1996). "Pyrrolidine-modified and 6-substituted analogs of nicotine: a structure–affinity investigation". European Journal of Medicinal Chemistry. 31 (11): 875–888. doi:10.1016/S0223-5234(97)89850-9.
  16. ↑ Effah, F.; Sun, Y.; Friedman, A.; Rahman, I. (1 February 2025). "Emerging nicotine analog 6-methyl nicotine increases reactive oxygen species in aerosols and cytotoxicity in human bronchial epithelial cells". Toxicology Letters. 405: 9–15. Bibcode:2025ToxL..405....9E. doi:10.1016/j.toxlet.2025.01.007. PMC  11875870. PMID   39894318.
  17. ↑ Qi, H.; Chang, X.; Wang, K.; Xu, Q.; Liu, M.; Han, B. (2023). "Comparative analyses of transcriptome sequencing and carcinogenic exposure toxicity of nicotine and 6-methyl nicotine in human bronchial epithelial cells". Toxicology in Vitro. 93 105661. Bibcode:2023ToxVi..9305661Q. doi:10.1016/j.tiv.2023.105661. PMID   37586650.
  18. 1 2 Jabba, S. V.; Jordt, S. E. (10 August 2024). "Marketing of nicotinamide as nicotine replacement in electronic cigarettes and smokeless tobacco". Tobacco Prevention & Cessation. 10: 1–5. doi:10.18332/tpc/187767. PMC   11295357 . PMID   39132445.
  19. ↑ "Nixodine-S Salt". Nicotine River. Retrieved 8 September 2025.
  20. ↑ Advisory values for nicotine and 6-methylnicotine in emissions from nicotine products without tobacco (PDF) (Report). RIVM (Netherlands). June 2025. Retrieved 8 September 2025.
  21. ↑ "ACMS #47 and Joint ACMS-ACCS #40 meetings, June 2025 – Pre-meeting public notice" (PDF). Therapeutic Goods Administration. 17 April 2025. Retrieved 8 September 2025.
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