Synthetic nicotine has arrived

Abstract

The introduction of a new product line of the popular disposable electronic cigarette brand Puffbar, advertised as containing synthetic nicotine, has drawn attention to the increasing use of synthetic nicotine in marketed products and its uncertain regulatory status. A search of the Truth Tobacco Industry Documents revealed that the industry considered using synthetic nicotine already in the 1960s, efforts that were abandoned due to high costs and insufficient purity. Recent patents revealed renewed efforts to develop more efficient strategies for the synthesis of nicotine. Nicotine exists as two stereoisomers, S-nicotine and R-nicotine. While S-nicotine is the prevalent (>99%) form of nicotine in tobacco, a market-leading form of synthetic nicotine contains both stereoisomers at equal amounts, raising concerns about inaccurate labelling and the poorly understood health effects of R-nicotine. Other manufacturers, including a leading vendor of pharmaceutical grade nicotine, developed stereospecific strategies to synthesise pure S-nicotine, now added to electronic cigarette products marketed in the USA and UK. While S-nicotine and R-nicotine can be differentiated by enantioselective High Performance Liquid Chromatography (HPLC), differentiation of synthetic (fossil-derived) from tobacco-derived S-nicotine will require development of methods to measure carbon isotope (¹⁴C or ¹³C) content. Vendors claim that the FDA has no authority to regulate synthetic nicotine as a tobacco product, allowing them to circumvent the premarket tobacco product application process. However, legal analysis suggests that FDA may have the authority to regulate synthetic nicotine as a drug. Alternatively, Congress needs to include nicotine from any source within the legal definition of tobacco products.

Keywords: electronic nicotine delivery devices; nicotine; non-cigarette tobacco products; tobacco industry; toxicology.

Figure 1

Products containing synthetic nicotine. (A) Puffbar line of electronic cigarettes containing synthetic nicotine, marketed since February 2021. (B) Next Generation Labs’ description of synthetic nicotine. (C) 20ne nicotine pouches with warning label stating synthetic nicotine content, available for ordering on Amazon.com.

Figure 2

Structure and chemistry of synthetic nicotine. (A) Structures of S-nicotine and R-nicotine. The chiral centre of nicotine is labelled with a red asterisk. In tobacco leaf, >99% of nicotine is present as S-nicotine. Synthetic ‘Tobacco-Free Nicotine’ (TFN), marketed by Next Generation Labs, is racemic, containing 50% S-nicotine and 50% R-nicotine. Pure synthetic S-nicotine is chemically indistinguishable from S-nicotine purified from tobacco. (B) Stereoselective synthesis of S-nicotine as described in a patent assigned to Zanoprima involving a biotechnological step. The starting material is myosmine, first stereoselectively converted to S-nornicotine using a recombinant enzyme (1), a NADH/NADPH-dependent imine reductase. S-nornicotine is then converted to S-nicotine through methylation (2).