There are no known additives that are addictive by themselves, and no known instances of the industry directly adding nicotine to tobacco products.1 However, tobacco product additives can amplify the effects of nicotine on the brain.
Nicotine is the main addictive chemical in tobacco, produced by the tobacco plant. Once dried tobacco is lit and inhaled, nicotine moves rapidly from the smoke into the bloodstream, via the lungs, then into most regions of the body. The addictive effects of nicotine come from its binding to cellular receptors in the brain, triggering the dopaminergic reward system (see Section 6.3 for more details).
There are numerous ways,1 described below, in which tobacco product additives may increase the addictive effects of nicotine.
12.6.2.1 Additives that increase the bioavailability of nicotine
The bioavailability of nicotine is the proportion of the nicotine from emissions that moves into the blood circulation. The bioavailability of nicotine from cigarettes is high, with 80 to 90% of nicotine in cigarette smoke being absorbed through the lungs into the blood stream.2
Menthol is an additive that alters nicotine metabolism, making it remain in the body for longer and sustaining its effect on the central nervous system. See Section 12.7 for more details.
It is possible that decreasing the acidity of tobacco emissions can increase the amount of nicotine entering the blood. Biological evidence suggests that reduced acidity increases absorption of nicotine through the mouth, however evidence about the effects on nicotine absorbed through the lungs is less clear (see Section 12.4.3.1).
Addition of ammonia or ammonium compounds to tobacco products is common. Ammonia can decrease the acidity of smoke and this might be increasing nicotine bioavailability.1,3,4 But it remains uncertain whether added ammonia in cigarettes increases the amount of nicotine in the blood as there is a lack of direct biological evidence. Ammonium compounds decompose to release ammonia, a gas that is highly water soluble, into the smoke. Ammonium bicarbonate, diammonium phosphate and urea are commonly added to tobacco products, with reconstituted tobacco5 serving as a source of ammonia, in addition to ammonia itself.3
Addition of sugars as flavours can increase the acidity of tobacco smoke, possibly reducing nicotine bioavailability. Ammonia may be added to counteract this increase in acidity.1
Studies conducted and published by the tobacco industry claim that ammonia does not affect blood nicotine levels.6,7 However, these studies are criticised for using cigarettes that already have high levels of ammonia in the tobacco filler, reducing the expected differences between cigarettes with and without added ammonia, and for using “low ammonia” cigarettes that had high percentages of Burley tobacco, which can increase the pH of smoke.8,9 One study that was independent of the tobacco industry also showed no difference in blood nicotine levels when high and low ammonium cigarettes were smoked.10
The World Health Organization’s (WHO) 2015 5 th Report of the Scientific Basis of Tobacco Product Regulation argues that the rate of nicotine absorption is more important than the total amount of nicotine absorbed. An important factor in reinforcing nicotine dependence is the uptake rate and the concentration spike within 10 seconds of the first puff.9,11 Whether nicotine uptake rate is affected by added ammonia or ammonium compounds is currently unknown.
The tobacco industry claims that—rather than to increase the bioavailability of nicotine—ammonia is added as a flavour or ‘binding’ agent, which would provide structural stability to the filler.5 Despite this claim, many documents released by the industry as part of settlement agreements for litigation describe the ‘augmentation of the impact of nicotine’ through the addition of ammonia or ammonium compounds.5 How ammonia is having this effect is not well understood.
12.6.2.2 Additives that increase the addictiveness of nicotine
Sugars are commonly added to tobacco products as flavourings. During the burning of a cigarette, sugars are converted into various aldehydes (see Section 12.4.3.2) by chemical reactions.12 One of these aldehydes, called acetaldehyde, may increase the addictiveness of nicotine.13 Additionally, acetaldehyde is also a carcinogen and respiratory toxicant.
Animal experiments show that acetaldehyde can increase the activity of nicotine in the brain, but not by increasing the amount of nicotine that enters the brain.13,14 This is described as a reinforcing effect. Experiments in animals conducted by Philip Morris showed that the combination of nicotine and acetaldehyde results in a rewarding effect, the extent of which exceeds the additive effects of each substance.1 Potential mechanisms for this effect of acetaldehyde include its involvement in chemical reactions that produce molecules that mimic neurotransmitters (signalling molecules in the brain) and therefore promote addictiveness, and by leading to the formation of chemicals that inhibit a crucial brain enzyme called monoamine oxidase.1,15
There is a lack of experimental evidence in humans for the effects of acetaldehyde from additives on nicotine and addiction. Tobacco, particularly the Virginia variety, contains high levels of sugars, as well as polysaccharides and cellulose that form acetaldehyde upon burning of a cigarette. It is unclear whether the addition of sugars to tobacco leads to a significant increase in acetaldehyde levels. Furthermore, little of the acetaldehyde produced during burning is believed to enter the blood stream. Ultimately the research on additives that produce acetaldehydes and their ability to increase the effects of nicotine in humans is inconclusive.1
Interestingly, a lozenge-delivered inhibitor of acetaldehyde showed some promise for increasing quitting of cigarettes in a small randomised controlled trials.16,17
Added menthol increases the addictiveness of nicotine by its effect on the central nervous system and possibly by altering nicotine metabolism. See Section 12.7 for more details.
12.6.2.3 Additives that facilitate the inhalation of tobacco smoke
It has been proposed that increasing bronchodilation (opening up the airways more) could enable the smoker to inhale deeper, therefore inhale a larger volume of smoke.
Added menthol or thymol (a very similar molecule to menthol) facilitate deeper inhalation of smoke, potentially increasing the addictiveness of nicotine indirectly. See Section 12.7 for more details.
Additives such as theobromine (made from cocoa) and eucalyptol may also increase bronchodilation. However, there is no evidence for this from biological experiments and the levels of these chemicals in smoke are relatively low.18
References
1. Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Addictiveness and attractiveness of tobacco additives. Brussels, Belgium 2010. Available from: http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_031.pdf.
2. Hukkanen J, Jacob P, and Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacological Reviews, 2005; 57(1):79-115. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15734728
3. Willems EW, Rambali B, Vleeming W, Opperhuizen A, and van Amsterdam JGC. Significance of ammonium compounds on nicotine exposure to cigarette smokers. Food and Chemical Toxicology, 2006; 44(5):678-88. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16288944
4. Pankow JF, Mader BT, Isabelle LM, Luo W, Pavlick A, et al. Conversion of nicotine in tobacco smoke to its volatile and available free-base form through the action of gaseous ammonia. Environmental Science & Technology, 1997; 31:2428–33. Available from: https://pubs.acs.org/doi/full/10.1021/es970402f
5. Stevenson T and Proctor RN. The secret and soul of marlboro: Phillip Morris and the origins, spread, and denial of nicotine freebasing. American Journal of Public Health, 2008; 98(7):1184-94. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18511721
6. Callicutt CH, Cox RH, Hsu F, Kinser RD, Laffoon SW, et al. The role of ammonia in the transfer of nicotine from tobacco to mainstream smoke. Regulatory Toxicology and Pharmacology, 2006; 46(1):1-17. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16875767
7. McKinney DL, Gogova M, Davies BD, Ramakrishnan V, Fisher K, et al. Evaluation of the effect of ammonia on nicotine pharmacokinetics using rapid arterial sampling. Nicotine & Tobacco Research, 2012; 14(5):586-95. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22140146
8. Inaba Y, Uchiyama S, and Kunugita N. Spectrophotometric determination of ammonia levels in tobacco fillers of and sidestream smoke from different cigarette brands in Japan. Environmental Health and Preventive Medicine, 2018; 23(1):15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29703135
9. WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation: Fifth report of a WHO study group. WHO Technical Report Series, Geneva: WHO, 2015. Available from: https://www.who.int/publications/i/item/who-study-group-on-tobacco-product-regulation-report-on-the-scientific-basis-of-tobacco-product-regulation-fifth-report-of-a-who-study-group.
10. van Amsterdam J, Sleijffers A, van Spiegel P, Blom R, Witte M, et al. Effect of ammonia in cigarette tobacco on nicotine absorption in human smokers. Food and Chemical Toxicology, 2011; 49(12):3025-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22001171
11. Samaha AN and Robinson TE. Why does the rapid delivery of drugs to the brain promote addiction? Trends in Pharmacological Sciences, 2005; 26(2):82-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15681025
12. Talhout R, Opperhuizen A, and van Amsterdam JG. Sugars as tobacco ingredient: Effects on mainstream smoke composition. Food and Chemical Toxicology, 2006; 44(11):1789-98. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16904804
13. Belluzzi JD, Wang R, and Leslie FM. Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology, 2005; 30(4):705-12. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15496937
14. Cao J, Belluzzi JD, Loughlin SE, Keyler DE, Pentel PR, et al. Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral, endocrine, and neuronal responses to nicotine in adolescent and adult rats. Neuropsychopharmacology, 2007; 32(9):2025-35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17287824
15. Talhout R, Opperhuizen A, and van Amsterdam JG. Role of acetaldehyde in tobacco smoke addiction. European Neuropsychopharmacology, 2007; 17(10):627-36. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17382522
16. Syrjanen K, Salminen J, Aresvuo U, Hendolin P, Paloheimo L, et al. Elimination of cigarette smoke-derived acetaldehyde in saliva by slow-release l-cysteine lozenge is a potential new method to assist smoking cessation. A randomised, double-blind, placebo-controlled intervention. Anticancer Research, 2016; 36(5):2297-306. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27127136
17. Syrjanen K, Eronen K, Hendolin P, Paloheimo L, Eklund C, et al. Slow-release l-cysteine (acetium(r)) lozenge is an effective new method in smoking cessation. A randomized, double-blind, placebo-controlled intervention. Anticancer Research, 2017; 37(7):3639-48. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28668855
18. Sokol NA, Kennedy RD, and Connolly GN. The role of cocoa as a cigarette additive: Opportunities for product regulation. Nicotine & Tobacco Research, 2014; 16(7):984-91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24610479