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.”