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.”

 

 

 

Imaginary Hobgoblins From E-Cigarette Liquid Lab Tests

As a pathologist, I have studied how human cells are altered by disease; with colleagues, I have explored in the laboratory how cancer cells behave and respond to various treatments.  A single human disease can involve thousands of changes in the arrangement and interaction of the 10,000 different kinds of molecules present in each cell. 

While I have profound respect for those conducting legitimate research to expand our understanding of human biology, diseases and their treatment, I am dismayed by the recent spate of laboratory studies in which researchers expose cells living in artificial environments to e-cigarette liquids.  The liquids invariably produce measurable effects, which lead to claims that e-cigarettes cause myriad diseases.  These claims are further exaggerated in press releases and sensationalized media coverage.

E-cigarette consumers – vapers – need to understand that what happens in these lab experiments does not necessarily mirror cellular action in humans.  Human cells nurtured in labs’ artificial environments are exquisitely delicate; even under perfect conditions, it is exceedingly difficult to keep them alive – a minor change in the environment can skew an experiment and even kill the cells.

Humans are far more resistant to small doses of chemicals than are cells in a petri dish.  Famed biologist Bruce Ames wrote in 2000, “Humans have many natural defenses that buffer against normal exposures to toxins…Examples of general defenses include the continuous shedding of cells exposed to toxins. The surface layers of the mouth, esophagus, stomach, intestine, colon, skin and lungs are discarded every few days; DNA repair enzymes, which repair DNA that was damaged from many different sources; and detoxification enzymes of the liver and other organs.” (abstract here).

Ames made prescient comments about excessive regulation based on laboratory experiments: “Regulatory efforts to reduce low-level human exposures to synthetic chemicals because they are rodent carcinogens are expensive; they aim to eliminate minuscule concentrations that now can be measured with improved techniques.  These efforts are distractions from the major task of improving public health through increasing scientific understanding about how to prevent cancer (e.g., what aspects of diet are important), increasing public understanding of how lifestyle influences health, and improving our ability to help individuals alter their lifestyles.  Why has the government focused on minor hypothetical risks at huge cost? A recent article in The Economist had a fairly harsh judgment:

“‘Predictions of ecological doom, including recent ones, have such a terrible track record that people should take them with pinches of salt instead of lapping them up with relish.   For reasons of their own, pressure groups, journalists and fame-seekers will no doubt continue to peddle ecological catastrophes at an undiminishing speed… Environmentalists are quick to accuse their opponents in business of having vested interests.  But their own incomes, their fame and their very existence can depend on supporting the most alarming versions of every environmental scare.  ‘The whole aim of practical politics’ said H.L. Mencken, ‘is to keep the populace alarmed — and hence clamorous to be led to safety — by menacing it with a series of hobgoblins, all of them imaginary.’  Mencken’s forecast, at least, appears to have been correct.’

“Aaron Wildavsky discusses worst-case risk assessment in his book But Is It True: A Citizen’s Guide to Environmental Health and Safety Issues: ‘We should be guided by the probability and extent of harm, not by its mere possibility.  The search for possibilities is endless and it trivializes the subject.  There is bound to be great diversion of resources without reducing substantial sources of harm.  Consternation is created but health is not enhanced…Weak causes are likely to have weak effects. Our search should be for strong causes with palpable effects, like cigarette smoking.  They are easier to find and their effects are much more important to control…The past necessity of proving harm has been replaced by a reversal of causality: now the individuals and businesses must prove that they will do no harm. My objection to this…is profound: our liberties are curbed and our health is harmed.’” (emphasis mine)

If lab studies were the standard for evaluating consumer products, then medicines already on the market would be in big trouble: One study found that half of marketed pharmaceuticals demonstrate cancer-producing properties in lab studies (here).  A Journal of Pharmacology report terms standard human cell lab tests (genotoxicity assays) “misleading,” “irrelevant” or “false.” (here)  

E-cigarette liquids are being vilified through such tests.  Vapers should not be fooled by the irresponsible transformation of weak cause-and-effect analyses into hypothetical illnesses.  Largely harmless products can be portrayed quite readily as dangers – coffee, for example , has not been linked to any serious disease, but one could point to lab studies showing that coffee kills cells (here and here) and promotes cancers (here).  These claims would have about as much scientific credibility as the current claims against e-cigarettes.