Population Evidence For & Against Menthol Addictiveness

 

Last week I reviewed the FDA’s evidence concerning menthol’s possible role in furthering addiction, as discussed in the agency’s proposed menthol ban.  I noted that the FDA rationale “is primarily based on nicotine and menthol experiments on rats and mice, plus laboratory tests on tissue samples.  The FDA presents no evidence for menthol’s effects on actual smokers.”

One individual responded to my post by arguing that evidence shows that menthol can enhance addictiveness in humans; they provided a link to a single study.

There is, in fact, considerable population-based evidence of the effects of menthol smoking on addiction in humans, but the FDA failed to cite any of that, likely because the evidence is entirely contradictory.  While some studies show that menthol enhances addictiveness, other studies indicate the opposite.  A single study sometimes offers both positive and negative findings.

The FDA conducted its own review (available here) of the literature on this subject, spanning the period 1980 to April 30, 2021.  In its proposed ban, the FDA published these conclusions:

“The weight of evidence supports that the sensory effects of menthol contribute to positive smoking experiences that facilitate repeated use. Evidence also supports that menthol in
cigarettes is associated with progression to regular cigarette smoking in youth and young adults and greater dependence in youth. However, evidence is not sufficient to support a conclusion of an association of menthol in cigarettes with dependence among adults due to inconsistent findings.  Similarly, evidence is not sufficient to support a conclusion of an association of menthol in cigarettes with altered smoking topography. In the case of cessation, the weight of evidence suggests that menthol in cigarettes is likely associated with reduced cessation success in the general population and is associated with reduced cessation success among Black cigarette smokers.”

Thus, even the FDA acknowledges the lack of convincing evidence to support an outright menthol ban.  While the agency points to effects in youth and young adults, smoking has almost disappeared among both groups (here and here). 

More mixed results have been published since the FDA’s April 2021 research cut-off, including a comprehensive review that found:

“Forty-three demographically adjusted studies (22 rated 'good', 20 rated 'fair', and one study rated 'poor' individual study quality) comparing menthol and non-menthol smokers were qualitatively synthesized across the following measures (study count; strength of evidence): duration of abstinence (2; low); quit attempts (15; insufficient); rate of abstinence/quitting (29; moderate); change in smoking quantity/frequency (5; insufficient); and, return to smoking/relapse (2; insufficient). Overall, the qualitative synthesis failed to show a consistent trend for an association between menthol cigarette use and smoking cessation across outcomes. Meta-analyses found no difference between menthol and non-menthol cigarette use and either quit attempts or abstinence.” (emphasis added)

The population evidence is clear: The addictive action of menthol remains ambiguous.

Where is the Evidence for Increased Menthol Addictiveness in the FDA Proposed Rule?

 

Commenting on the FDA’s proposed rule banning menthol cigarettes, a recognized tobacco policy expert argues that while a menthol cigarette ban was justified, the agency ought not prohibit menthol in smoke-free tobacco products. 

Clifford Douglas, director of the University of Michigan Tobacco Research Network, writes: “Menthol also interacts with nicotine in the brain to increase addiction.”  I was under the assumption that the addictive action of menthol was still questionable, so I explored the topic.

The FDA’s proposed rule includes this evidence passage:

“In addition to its flavor and sensory effects, menthol contributes to a greater risk of nicotine dependence by enhancing the addictive effects of nicotine in the brain by affecting mechanisms involved in nicotine addiction (Refs. 10-13).  Clinical data show that menthol cigarette smokers have higher levels of brain nicotinic receptors compared to non-menthol smokers (Ref. 14).  Studies demonstrate that menthol, like nicotine, binds to nicotinic receptors in the brain (Refs. 15 and 16), and menthol alone can increase the number of nicotinic receptors in the brain (Refs. 10 and 11). Evidence demonstrates that the combined effects of menthol and nicotine in the brain are associated with behaviors indicative of greater addiction to nicotine compared to nicotine alone (Refs. 10 and 12).”

I list the references and key findings below.  In summary, four of the seven studies were in mice or rats (Refs. 10-13); one was a lab study using human tissue (Ref. 16); one was a literature review (Ref. 15).  Only a single study (Ref. 14) involved human smokers, who were PET scanned after receiving an injection of 2-[¹⁸F]fluoro-A-85380 (2-FA).  The main finding in this study was “menthol smokers having 9–28% higher α₄β₂* nAChR densities than non-menthol smokers across regions.”  I don’t think this is proof that menthol increases addiction.

In summary, the FDA’s evidence for menthol furthering addiction is primarily based on nicotine and menthol experiments on rats and mice, plus laboratory tests on tissue samples.  The FDA presents no evidence for menthol’s effects on actual smokers.

 

FDA References for Menthol Aiding Addictiveness in Cigarettes

10. Alsharari, S.D., J.R. King, J.C. Nordman, et al. “Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice.” PLoS ONE, 10(9):e0137070, 2015.
Available at https://doi.org/10.1371/journal.pone.0137070.

“Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine’s clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment.”

11. Henderson, B.J., T.R. Wall, B.M. Henley, et al. “Menthol Alone Upregulates Midbrain Nachrs, Alters Nachr Subtype Stoichiometry, Alters Dopamine Neuron Firing
Frequency, and Prevents Nicotine Reward.” The Journal of Neuroscience, 36(10):2957-2974, 2016. Available at https://doi.org/10.1523/JNEUROSCI.4194-15.2016.

“We investigated the effect of long-term menthol alone on midbrain neurons containing [nicotinic acetylcholine receptors] nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation.”

12. Henderson, B.J., T.R. Wall, B.M. Henley, et al. “Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in Nachr Function, Nachr
Upregulation, and Da Neuron Excitability.” Neuropsychopharmacology, 42:2285-2291, 2017.
Available at https://doi.org/10.1038/npp.2017.72.

“Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone.”

13. Zhang, M., E. Harrison, L. Biswas, et al. “Menthol Facilitates Dopamine-Releasing Effect of Nicotine in Rat Nucleus Accumbens.” Pharmacology, Biochemistry and Behavior,
175:47-52, 2018. Available at https://doi.org/10.1016/j.pbb.2018.09.004.

“The present study used intracranial microdialysis to examine whether and the ways in which menthol affects nicotine-induced dopamine release in rats in the nucleus accumbens core (NAc), a terminal field of brain reward circuitry… male Sprague-Dawley rats were first trained in 20 daily 1-h sessions to press a lever for intravenous nicotine self-administration (15 μg/kg/infusion). Dopamine levels were then measured in the right NAc using intracranial microdialysis coupled with high-performance liquid chromatography. Five minutes before microdialysis, the rats received an intraperitoneal injection of menthol (0, 1, 2.5, and 5 mg/kg), a subcutaneous injection of nicotine (0.2 mg/kg or its vehicle), or both. Menthol alone did not affect dopamine levels in dialysates, whereas nicotine alone elevated dopamine levels.”

14. Brody, A.L., A.G. Mukhin, J.L. Charite, et al. “Up-Regulation of Nicotinic Acetylcholine Receptors in Menthol Cigarette Smokers.” International Journal of
Neuropsychopharmacology, 16(5):957-966, 2013. Available at
https://doi.org/10.1017/S1461145712001022.

This was a human study: “In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9–28% higher α₄β₂* nAChR densities than non-menthol smokers across regions.”

15. Wickham, R.J. “The Biological Impact of Menthol on Tobacco Dependence.” Nicotine & Tobacco Research, 22(10):1676-1684, 2020. Available at https://doi.org/10.1093/ntr/ntz239.

This was a literature review containing 101 references.

16. Shahoei, R. and E. Tajkhorshid. “Menthol Binding to the Human Α4Β2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in The Membrane.” Journal of
Physical Chemistry, 124(10):1866−1880, 2020. Available at
https://doi.org/10.1021/acs.jpcb.9b10092

“We utilize various computational methodologies to study menthol’s interaction with multiple organic phases, a lipid bilayer, and the human α4β2 nicotinic acetylcholine receptor (nAChR), the most abundant nAChR in the brain.”

 

 

 

FDA Unveils New Smoker Numbers to Justify a Menthol Ban

 

In its proposed rule to ban menthol cigarettes, the FDA makes a bizarre claim: “In 2019, there were more than 18.5 million current smokers of menthol cigarettes ages 12 and older in the United States.”

The agency derived this number from the National Survey on Drug Use and Health (NSDUH), which reported that 18.3 million adults and 260,000 youth 12-17 years old smoked menthol cigarettes in 2019.

Using that same survey, however, the total number of smokers in 2019 was 46.2 million -- 45.6 million adults and 600,000 youth age 12-17.

No federal official or agency has ever suggested there were that many smokers in 2019.  The CDC and the FDA only acknowledged the existence of 34 million adult smokers and 886,000 youth smokers, using the National Health Interview Survey (NHIS) and National Youth Tobacco Survey (NYTS), respectively. 

The CDC and FDA use the NYTS youth number (886,000), which is nearly 50% higher than the 600,000 reported by the NSDUH.  This is further evidence of why the NYTS numbers should never be the final word for youth tobacco use (here and here). 

Using the FDA’s NSDUH number for adult smokers, the comparison with the NHIS number it formerly used is almost as bad, and in the opposite direction.  Now the agency menthol claim implies that there were 45.6 million adult smokers in 2019 (NSDUH), but before it only acknowledged 34 million (NHIS).

What did the FDA do with 286,000 youth and 11.6 million adult smokers?

When they want to emphasize big smoking numbers, the FDA and CDC use NSDUH and NYTS data.  When they prefer smaller numbers, they use the NHIS.  I have highlighted this deception since 2009. 

It is time to hold these agencies accountable, especially when the FDA uses this manipulation to justify punitive regulation.