Spree Bar, a vaping system delivering a synthetic nicotine analogue, marketed in the USA as ‘PMTA exempt’

Background

In February 2021, the popular vaping company, PuffBar, started selling disposable e-cigarettes in the United States containing synthetic nicotine, claiming to be exempt from federal and state laws regulating products containing tobacco-derived nicotine. [1] United States lawmakers responded to the emerging synthetic nicotine market by clarifying that synthetic nicotine products are subject to the U.S. Food and Drug Administration’s regulatory regime for tobacco products. [1-3] As of April 14, 2022, the FDA has been authorized to regulate tobacco products containing nicotine from any source, including laboratory synthesis, requiring manufacturers to submit a premarket tobacco product application (PMTA).[3] In October 2022, the FDA sent a warning letter to the company, alerting the owners that its products are “marketed unlawfully and are subject to enforcement action at FDA’s discretion”. [4 5] Currently, the company appears to be selling Puffbar-branded e-cigarette products without nicotine only. [6]

While many countries have updated their tobacco product laws to cover synthetic nicotine, or are in the process of doing so, a recent World Health Organization (WHO) report warned that non-nicotine tobacco alkaloids or synthetic nicotine analogs could be used by manufacturers to bypass regulatory schemes focusing on nicotine alone.[2] Non-nicotine tobacco alkaloids such as anabasine, nornicotine, anatabine and myosmine have well known addictive and reinforcing effects. [7-10] Starting in the 1970s, tobacco companies also developed various synthetic nicotine analogs and studied whether they could be used to dissociate nicotine’s central and peripheral effects, to create more desirable products, to circumvent regulation, or to develop pharmaceuticals. [11] The tobacco companies, however, never used these synthetic nicotine analogs in commercial products until now.

Spree Bar, a “PMTA exempt” electronic cigarette system

The concern that companies might use synthetic nicotine analogs in order to avoid regulation is no longer hypothetical. As of October 2023, vape stores in the United States had started selling a new electronic cigarette pod system named Spree Bar, advertised as “PMTA exempt” (figure 1).[12] Spree Bar products are promoted through convenience store advertising and web channels, using youth- and young adult-appealing artificial intelligence-generated characters (figure 1). The products are marketed as containing “Metatine”, a trademarked name for a synthetic nicotine analog (figure 2).[13-15] The trademark name owner and wholesaler of Spree Bar, Charlie’s Holdings Inc. (Costa Mesa, CA), states:

Figure 1.

Screen shot of the Spree Bar website taken on 10/08/2023, with a statement claiming that the products are “PMTA exempt”. [12]

Figure 2.

Section of a screen shot of the Metatine website taken on 09/23/2023, stating that products containing the active ingredient, 6-methyl nicotine, do not meet the definition of “tobacco product” in the Federal Food, Drug and Cosmetic Act, and do not require a PMTA to be sold in the US. [17]

“SPREE BAR is pre-filled with flavored e-liquid containing proprietary Metatine^™.

Metatine is a synthetically derived molecule that is structurally similar to, but chemically different from, other vaping alkaloids. Although Metanine [sic] produces the same sensation as nicotine and may also be addictive, Metatine is not made or derived from tobacco or nicotine, and Metatine does not consist of or contain nicotine from any source.

SPREE BAR products containing Metatine (and no tobacco-derived materials or nicotine) do not meet the definition of a “tobacco product” in the Federal Food, Drug, and Cosmetic Act and do not require a Pre-Market Tobacco Application (PMTA) to be sold in the US. ”.[12]

The wholesaler also claims that selling Spree Bar products would allow vendors to keep more profits since they cannot be taxed as tobacco products: “Metatine products are exempt from nicotine excise taxes in many states, which can result in massive savings for retailers and consumers. Metatine can be combined with many flavors and is legal to sell in nearly all 50 states.”.[16]

Charlie’s Holdings explicitly stated that it was using a synthetic nicotine analog in Spree Bar, rather than nicotine itself, in order to avoid FDA regulation. The company further explained that it had abandoned its pending PMTA submissions for its nicotine-containing e-cigarette products and was instead focusing on Spree Bar because it was “frustrated” by the pace of the FDA’s PMTA reviews and by the fact that “no company in the world, to date, has received an FDA marketing order for a flavored disposable vape product.” [14]

“Metatine” (6-Methyl nicotine) as a nicotine replacement: toxicology and addictiveness

“Charlie’s Holdings Inc., the supplier of Spree Bar, established a website with the address “metatine.com” stating that:

“The substance Metatine^™ has the International Union of Pure and Applied Chemistry (IUPAC) designation 2-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]pyridine ….”.[17]

2-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]pyridine is synonymous with (S)-6-methyl nicotine (Chemical Abstracts Number: CAS 13270-56-9) (figure 3).[18] 6-methyl nicotine is a structural analogue of nicotine (figure 3), with a methyl group substitution at position 6 of nicotine’s pyridine ring. Recently awarded patents describe new synthesis protocols to generate 6-methyl nicotine from petrochemical precursors.[19-21] One such patent was assigned to Shenhzen Zinwi Biotech, a leading e-liquid company that also sponsored a toxicological study at Guangdong Pharmaceutical University. This study reported that 6-methyl nicotine has increased cytotoxicity compared to nicotine in a permanent human bronchial epithelial cell line (BEAS-2B), but milder effects on the upregulation of lung cancer-related proteins. [19 22] The authors conclude “that new electronic cigarettes with 6-MN might offer some advantages over conventional electronic cigarettes containing nicotine”, providing evidence that the sponsoring company is seeking to encourage use of the compound, 6-methyl nicotine (abbreviated as 6-MN), in e-cigarettes.[22] However, no toxicological data in humans are available for 6-methyl nicotine, and in vivo study in rats revealed that the 50% lethal dose (LD₅₀) for 6-methyl nicotine is at least 1.5 - 3-fold lower than for nicotine, suggesting that 6-methyl nicotine is more toxic than nicotine [23 24].

Figure 3.

Chemical structures of (S)-nicotine (left), the major form of nicotine in tobacco, and (S)-6-methyl nicotine (right), trademarked as “Metatine”, with a methyl group substitution (blue) at position 6 of the pyridine ring (positions numbered in green). The red asterisk indicates the chiral center of nicotine.

Another patent, assigned to Shanghai Lingnuo Biotech Co Ltd., includes human studies in which e-cigarette users were asked to rate the “throat hit” and other psychophysical qualities of e-cigarette aerosol containing 6-methyl nicotine. [20] In one of these studies, 1 mg/ml 6-methyl nicotine was found to be as satisfying as 3 mg/ml nicotine and to produce a similar “throat hit”, with the authors concluding that “6-methyl nicotine can be used for replacing nicotine in electronic aerosolization”.[20] Only 10 test subjects participated in this study, with unknown background, with puffing protocols not mentioned, and with no statistical analysis provided.

While a manufacturer-sponsored study claimed that 6-methyl nicotine may be less addictive than nicotine, [22] previous pharmacological studies demonstrated that 6-methyl nicotine is 3-fold more potent at replacing [³H]nicotine from rat brain membranes and 5-times more potent at producing prostration behavior. [25] 6-methyl nicotine was found to be twice as potent as nicotine as an analgesic in the tail flick test, and 3.3 times as potent in increasing spontaneous motor activity. [26] Since these behaviors are triggered by nicotinic receptor activation, it can be supposed that 6-methyl nicotine is, in fact, more addictive than nicotine.

6-Methyl nicotine products in the United States marketplace

To our knowledge, Spree Bar is the first and, as of now, only product using 6-methylnicotine marketed in the United States and available for purchase by consumers. Spree Bar products and Metatine are discussed in Reddit posts, including initial user reports, suggesting increasing awareness by e-cigarette users in the United States.[27 28] The authors of the present study purchased Spree Bar products on 10/07/2023, receiving delivery on 10/17/2023, confirming availability in the United States.[29] We identified another company, Novel Compounds LLC (Cheyenne, WY), advertising 6-methylnicotine under the trademark “Imotine” as a wholesale product to manufacturers. [30-32] However, we did not identify any US-marketed products yet using this brand name version. An abstract presented by a US-based chemical analytical services company at a recent tobacco industry conference describes a method for the quantification of 6-methyl nicotine and detected its presence in e-liquids, confirming efforts by the industry to market such products.[33] Given the growing activity from several industry groups, we expect that additional 6-methyl nicotine-containing products will be marketed in the United States soon.

6-Methyl nicotine: Regulatory challenges and solutions

Are products containing 6-methyl nicotine, differing from nicotine by a methyl group, subject to the PMTA requirement and the other provisions of the U.S. Tobacco Control Act (TCA), or are they indeed “PMTA exempt”? The TCA, as amended in 2022, now covers products “made or derived from tobacco, or containing nicotine from any source.”. [34] The TCA defines “nicotine” as as: “12. Nicotine. The term 'nicotine' means the chemical substance named 3-(1-Methyl-2-pyrrolidinyl) pyridine or C[10]H[14]N[2], including any salt or complex of nicotine.” [35] 6-methyl nicotine has a different chemical formula C[11]H[16]N[2] and name. If the FDA concludes that 6-methyl nicotine is a “complex” of nicotine and takes enforcement action against Spree Bar or other similar products, the manufacturers would likely challenge that determination in court. [36] Other jurisdictions define the term “nicotine” differently. For example, Article 2 (Definitions) of the European Union’s Tobacco Products Directive (TPD) states: “(19) ‘nicotine’ means nicotinic alkaloids”. [37] The term “alkaloid” denotes both natural and synthetic nicotinic ligands, thus 6-methyl nicotine would fall within the scope of the EU’s TPD. [38]

Should the FDA (or a future court decision) conclude that 6-methyl nicotine is not “nicotine” within the meaning of the TCA, then it does not mean that products containing 6-methyl nicotine are necessarily exempt from all FDA regulation. A federal appeals court ruled in 2010 that “customarily marketed” nicotine-containing products cannot be regulated as drugs or drug-delivery devices if they are sold “without claims of therapeutic effect.” [39] However, that decision was based on the premise that these products would be subject to FDA regulation as tobacco products, and the case’s reasoning would not apply to products that do not fall within the TCA’s definition of a “tobacco product.” [39] The proclamations on Spree Bar’s website that Metatine “produces the same sensation as nicotine” and “may also be addictive,” combined with the similarity in chemical form to nicotine and evidence of similar physiological effects, strongly suggest that the FDA could alternatively seek to regulate the 6-methyl nicotine in Spree Bar as a drug under the Federal Food, Drug, and Cosmetic Act (FDCA).[40] If the FDA determines that 6-methyl nicotine is being marketed as a drug intended to produce particular physiological effects (the FDCA defines drugs in part as “articles (other than food) intended to affect the structure or any function of the body”)[41], then it would not be possible for it to be sold legally without the manufacturer first obtaining FDA approval.

When companies market products like Spree Bar as exempt from FDA regulation, it reduces confidence in the FDA’s regulatory scheme and undermines the FDA’s efforts to protect public health. The FDA should quickly announce its policy with respect to such products and take appropriate enforcement action. Congress might also consider clarifying that products containing non-nicotine tobacco alkaloids or synthetic nicotine analogues are tobacco products under U.S. law, by amending the TCA to expressly say as much. For example, it could follow the European Union’s approach and define “nicotine” to more broadly include all nicotinic alkaloids, thus enabling the FDA to regulate e-cigarette products containing 6-methyl nicotine the same way it regulates all other e-cigarette products. [37 38]