As I mentioned in a prior post, the tobacco / nicotine industry has adopted the analog strategy to stay ahead of government regulation and oversight. This involves, at present, substituting 6-methyl-nicotine (6-MN) for nicotine in a host of products including e-cigarette liquids and oral pouches. This strategy is not dissimilar to the strategy in the illicit drug markets, first in the 1980s when amphetamine analogs proliferated and then renewed ~2008 with a diversity of cathinone analogs (“bathsalts”) and cannabinoid receptor agonist drugs (“Spice”) appearing in various places including over the counter in convenience stores and head shops.
The oral nicotine pouch is similar to the Bandits familiar to my generation, which amounted to small amounts of tobacco (and additives) in a small material pouch similar to a teabag. This could then be held between cheek and gum less disgustingly than “chewing” tobacco or smokeless tobacco (e.g., Skoal, Copenhagen) products to deliver a buccal (gums) dose of nicotine.
The newest evolution of these products apparently eschews tobacco and simply puts nicotine (and now 6-MN) onto some sort of carrier material, along with various flavorants.
Jabba and colleagues have posted a pre-print on medrx Health Risk Assessment for an Unregulated Neurotoxic Nicotine Analogue in Oral Pouch Products (doi: https://doi.org/10.1101/2025.11.13.25340208 ) which analyzes the 6-MN content of several oral pouch products. They obtained 25 total flavored variants of three brands, Aroma King, MG and Hippotine and confirmed 6-MN content from about 3.28 mg to 14.48 mg per pouch. They assert this compares with 2-8 mg of nicotine in typical oral pouch products, and provide reference data on the nicotine content of two Zyn brand nicotine pouches (3.32 and 5.66 mg).
Interestingly, the manuscript reports that for the six products which listed a 6-MN content, the analyzed content per pouch was lower. On the order of under 40% of the advertised content. This matches up with this group’s prior report that the amount of 6-MN in commercial e-cigarette liquids was often lower than the packages advertised. Accumulation of these sorts of analyses can give an imprecise, but market-based, indication of the relative potency of the analog compared with nicotine.
The other thing about this manuscript is that a comment has been posted on the pre-print. This is supposed to be one of the advantages of posting pre-prints, i.e., the authors have a chance to address questions, comments and concerns before submitting it to peer review. Likewise, the reader has access to analysis. In this case, the commenter takes issue with a Risk Assessment, and in particular a Hazard Quotient, calculated by the authors. The comment reads:
The HQ calculations for heart rate increase are scientifically invalid. Heart rate increase from nicotinic agonists is the intended pharmacological effect, not an adverse outcome. The authors use an ARfD based on heart rate increases, but HQ methodology is designed to assess adverse health effects. Pharmacological receptor activation that produces the desired stimulant effect cannot be characterized as a toxicological hazard. By this logic, caffeine would have unacceptable HQs for increased alertness.Valid cardiovascular risk assessment requires identifying doses causing actual adverse outcomes like sustained tachycardia leading to arrhythmias, hypertensive crises, or cardiovascular events in vulnerable populations. The physiological response that constitutes the purpose of product use is not a safety threshold exceedance.
This read a little weird to me. I am almost certain that nobody uses nicotine for the primary outcome that it increases their heart rate. All appearances suggest people use nicotine for cognitive effects. For making them feel more alert, more focused. To suppress their appetite and to stave off tiredness. Of course, once they are addicted they use nicotine to avoid the unpleasant feelings associated with withdrawal. I have never run across any suggestion that the primary purpose or intent is to experience an increase in heart rate. This commenter then illustrates the tangled logic, by pointing out the desired effects of caffeine are alertness. Yes.
Now they do have a point that an elevation of heart rate may be an unintended effect that is not necessarily a health concern. And the obvious, albeit unstated, issue that the consumer may perform some sort of risk/benefit tradeoff and conclude that an elevated heart rate is worth whatever benefit they get from ingesting caffeine, nicotine, or the nicotine analog 6-MN.
The commenter then ends with
The conclusions about exceeding safety thresholds rest on this fundamental mischaracterization of pharmacology as toxicity. This undermines legitimate regulatory concerns about unregulated nicotine analogues. Meaningful risk assessment requires identification of true adverse cardiovascular outcomes, not normal receptor-mediated responses.
I don’t agree this is a “fundamental mischaracterization”. Intended and unintended pharmacological effects of various drugs can certainly be construed as toxicity. Information on the 6-MN content of oral products helps navigate regulatory concerns. The value of this calculated Hazard Quotient is perhaps up to the observer, but it doesn’t “undermine” anything. The rest of this, “meaningful” assessment of risk, “true” adverse outcomes… well that is in the eye of the beholder as well. What is important is to provide data where possible and to provide interpretation….and critique. So this is all part of the system working, in my view.
Now, as loathe as I usually am to play ad hominem games, I did do a quick google on the name left on the comment. There were a couple of links to that name which indicated their job is a Toxicologist at Altria.
Altria, of course, is the corporation that owns brands such as Philip Morris USA, U.S. Smokeless Tobacco Company and NJOY. Everyone should recognize Phillip Morris as a very large tobacco products company, indeed the creation of the Altria company was a re-brand of Phillip Morris Companies Inc. NJOY is a pod-style e-cigarette brand. U.S. Smokeless Tobacco Company is a big player in so-called moist oral tobacco products such as Copenhagen and Skoal. The Phillip Morris International brand was spun off at some point, and they are the sellers of Zyn oral pouches. Altria received FDA approval to market their nicotine oral pouch products in December 2025.
Suffice it to say, there is a long tradition of tobacco companies hiring supposed scientists and toxicologists to defend their selling of products which are adverse to health. When it comes to tobacco products, they have been playing this game for over 50 years and for the most part have been found to be disingenuous at best, and out and out fraudsters who conceal data that counters their claims to harmlessness at the worst.
This illustrates why we need to generate data, and lots of it. One or two or a dozen papers are not sufficient, particularly when each of them will get criticisms from industry employees who are highly motivated to downplay harms. This includes a need for study of the novel delivery products such as oral pouches and e-cigarettes as well as the chemicals that are in those devices such as flavorants (apple, cotton candy), so-called cooling agents (menthol, WS-3, WS-23) and nicotine analogs such as 6-methyl-nicotine.
Information is needed for individuals making decisions about which products to use or not use, for parents attempting to keep their adolescents from being addicted to nicotine and for public policy makers who may or may not pass laws and support regulations.
TL neuro 