InDepth 12C: Reducing the nicotine content of cigarettes

Last updated:  January 2022

Suggested citation: Greenhalgh, EM, Winnall, WR & Scollo, MM. InDepth 12C: Reducing the nicotine content of cigarettes. In Greenhalgh, EM, Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2023. Available


12C.1 Rationale for reducing the level of nicotine in cigarettes
12C.2 Development of low nicotine cigarettes
12C.3 Effects of reduced nicotine content cigarettes on smoking and health
12C.4 Public health considerations in implementing a nicotine reduction policy

12C.1 Rationale for reducing the level of nicotine in cigarettes

It is well established that addiction to nicotine maintains most smokers’ use of tobacco products.1 Once addicted, quitting can be extremely difficult, with many smokers repeatedly relapsing following their cessation attempts.2 Young people have a very poor understanding of addiction, often believing that they will be able to stop smoking at will.3 However, once they take up smoking,  addiction to tobacco delivered nicotine develops quite rapidly—See Section 6.13—sustains the behaviour into adulthood, dramatically increasing their risk of tobacco-related harm.4

The regulation of the maximum level of nicotine in tobacco products was first suggested in the mid-1990s as a potential strategy for avoiding the transition from experimental smoking to addiction.5, 6 Legal proceedings initiated against tobacco companies by US state attorneys general had revealed a great deal of evidence about the centrality of nicotine in industry efforts to maintain customers, despite concerns about the health effects of smoking.7, 8  Reducing the nicotine content in cigarettes so that they are non-addictive was proposed as a mechanism to prevent adolescents and occasional smokers from becoming addicted. A gradual reduction could also allow smokers to slowly decrease their intake of nicotine, thereby weaning themselves off the product and making quitting substantially easier.9, 10

While the idea for nicotine reduction fell out of favour in subsequent years, largely due to concerns about compensatory smoking, since 2010 researchers have taken a renewed interest in this proposal. Unlike ‘low tar and light’ cigarettes promoted by tobacco companies, which did not actually reduce delivery of tar and instead involved design features that allowed smokers to easily compensate for the reduced nicotine content by drawing harder (see Section, reduced nicotine cigarettes could be manufactured in the same manner as regular cigarettes but—in preference to regular tobacco—using tobacco that has a lower nicotine content. If the nicotine content was low enough, it would be virtually impossible to absorb significant levels of nicotine by using these products.10

12C.2 Development of low nicotine cigarettes

Initial proposals in the mid-1990s suggested a gradual reduction in nicotine in cigarettes to 0.5 mg per cigarette.9 Since then, several studies have established that a >95% reduction in nicotine, from about 10 to 15 mg/nicotine per conventional cigarette to  ≤0.4 mg nicotine/g tobacco per ‘very low nicotine content cigarette’, will likely reduce addictiveness11, 12 and dependence.13 Others have suggested that that cigarettes with slightly higher nicotine/g tobacco doses (‘reduced nicotine content cigarettes’) can also reduce the reinforcing effects of nicotine,14 with minimal differences between 2.4 and 0.4 mg nicotine doses15, 16 or between 1.3 and 0.4 mg/g.17 Nonetheless, most trials have examined responses to the 0.4 mg nicotine dose, leading to greater endorsement of very low nicotine content cigarettes as the product standard.18, 19

Production of low-nicotine cigarettes is quite feasible for the tobacco industry. Spectrum cigarettes, created for research purposes, can be made with very low nicotine levels, such as 0.4 mg/g of tobacco. Spectrum cigarettes have been used to demonstrate the feasibility of using low nicotine cigarettes to reduce reduced nicotine exposure, nicotine dependence and the number of cigarettes smoked.13 Experiments using Spectrum cigarettes have also demonstrated reductions in the levels of toxicant biomarkers in users. The lower the nicotine level of the spectrum cigarette, the lower the nicotine in the blood after use.20

One method for producing low-nicotine cigarettes products is to use tobacco plants that produce relatively low amounts of alkaloids, called low-alkaloid plants. These have been discovered in the past, having arisen from natural variation, as well as been produced by genetic modification of tobacco plants.21 An example of naturally-arising tobacco plant variation is the low-alkaloid variant of LA Burley 21, a genetically stable breeding line that was developed in the early 1930s from a Cuban cigar tobacco plant.22 Spectrum cigarettes, on the other hand, are made from genetically modified tobacco plants.

Nicotine is produced in the roots of tobacco plants and transported through the stems into the leaves, where it serves as a natural defence against pests. The protein products of numerous genes are involved in the biosynthesis of nicotine in tobacco plants and the regulation of this complex biological process.23 Genes called NIC1 and NIC2 are influential regulators of nicotine production. Disruption of the NIC1 gene (by naturally occurring DNA variations or those made by genetic modification) leads to tobacco plants that produce very low amounts of nicotine.23-25 Similar techniques have been used to generate low-alkaloid tobacco plants by disrupting the BBL gene.26 Importantly, other potentially addictive alkaloids such as anatabine, nornicotine and anabasine remained at low levels in these plants.26

Manufacturing techniques can also be used to reduce nicotine after harvesting of the plants. Over 90% of the nicotine content of plants can be removed by treatment with chemicals such as ammonia. However, this treatment also removes some of the flavours from the tobacco and can leave residual chemicals that may be toxic.21 Using a filter that removes much of the nicotine from cigarette smoke is another option for creating low-nicotine cigarettes.27

A number of low nicotine cigarettes have been sold in the past, such as the Quest brand, however these have not been commercially successful. Consumers have rated them as less satisfactory and less palatable.21 It is possible that alkaloids contribute somewhat to the taste of the tobacco, so reducing them leads to flavour changes that are unavoidable.21 The US FDA recently authorised the sale of a number of variants of reduced nicotine content cigarettes from 22nd Century Group. According to the company’s website, its products are created through genetic engineering, gene-editing, and modern plant breeding.28

12C.3 Effects of reduced nicotine content cigarettes on smoking and health

Studies modelling the public health impacts of lowering the nicotine content of cigarettes to minimally addictive levels have concluded that it would lead to substantial reductions in tobacco-related morbidity and mortality, both through decreasing uptake and increasing cessation.29, 30 One such study estimated that a reduced nicotine cigarette content standard implemented in the US in 1965—decades after patents and internal company documents from the 1920s and ‘30s first described methods to extract nicotine from tobacco—could have averted 21 million smoking attributable deaths (54% reduction) and 272 million life years lost (64% reduction) from 1965 to 2064.31 Following a recent announcement in New Zealand of a nicotine reduction strategy,32 a modelling study concluded that it is plausible that the policy could help achieve the Government’s goal of 5% smoking prevalence by 2025, particularly if it formed part of a comprehensive tobacco control program and targeted Maori smokers. However, the authors note that there is a high level of uncertainty with the findings.33

Research with adolescents and young adults has found that reduced nicotine cigarettes can decrease the positive subjective effects of smoking, and therefore may reduce abuse liability.34-36 A study with adolescent smokers found that reduced nicotine content cigarettes were less satisfying, and reduced withdrawal symptoms, negative affect, and craving.35 A major review found that one of the main benefits to public health of reducing nicotine would be decreasing uptake of regular smoking. Research to date suggests that reduced nicotine cigarettes may achieve this by reducing positive expectancies about smoking, and by reducing the likelihood of transitioning to regular smoking through making cigarettes inherently less reinforcing.37 Concerns that reduced nicotine content cigarettes might be more appealing to young people and/or might lead to compensatory smoking in youth have not been borne out by research.38

Among smokers, switching to reduced nicotine cigarettes can lead to a reduction in dependence,39, 40 consumption (i.e., the number of cigarettes smoked per day),37, 41, 42 and toxicant exposure, with minimal symptoms of nicotine withdrawal.13, 43-48 It may also increase the number and success of quit attempts.37, 49, 50 A common concern regarding low nicotine cigarettes is that smokers would engage in compensatory smoking—whereby smokers take more and deeper puffs from each cigarette, and smoke more of it, in order to obtain the same level of nicotine—resulting in minimal reductions in toxin exposure despite a reduction in cigarette consumption. However, studies have consistently shown that a reduction in nicotine content is unlikely to result in an increase in compensatory smoking.51-55 Compared to gradual reduction, immediate nicotine reduction appears to result in greater reductions in smoking behaviour and biomarkers of exposure56, 57 and in product satisfaction and cigarette reward value.58 After trialling the products, smokers have reported generally positive outcomes such as feeling less dependent59 and support for nicotine reduction policies.60-62 Studies have also shown that switching to very low nicotine content cigarettes leads to reduced demand for smokers’ usual-brand cigarettes63 and may also break the link between affect and smoking,64 indicating reductions in the reinforcing efficacy of cigarettes. Nonetheless, despite significant reductions in consumption and biomarkers of exposure with reduced nicotine content cigarettes, their use still carries significant health risks, highlighting their primary role as a step toward quitting.65 

Research also suggests that reduced nicotine cigarettes could equally benefit heterogeneous groups of smokers, including vulnerable or disadvantaged groups who are at greater risk of tobacco-related harm. Studies in smokers with mental illness and socioeconomic disadvantage have found that switching to reduced nicotine content cigarettes may improve respiratory health66 and reduce consumption and dependence.15, 67 In one study, low nicotine cigarettes elicited similar responses (in measures of consumption, dependence, and toxin exposure) across smokers regardless of indicators of disadvantage.68 Several randomised controlled trials found no differences in responses to very low nicotine cigarettes among young compared with older smokers,69, 70 and regardless of the education level, race,56 or gender.56, 71 Findings of additional studies suggest that such a policy may also benefit pregnant women who smoke72 as well as people with chronic health conditions,73 and may also help to reduce alcohol use and binge drinking among smokers.74 Responses to nicotine reduction appear to be largely similar regardless of individual differences in nicotine metabolism and dependence.75 A review published in 2021 similarly concluded that this policy could benefit those with psychiatric comorbidities, those who use other substances, those with low socioeconomic status, young people, people who smoke infrequently and people who prefer menthol cigarettes.37

12C.4 Public health considerations in implementing a nicotine reduction policy

Developing low-nicotine cigarettes has been a prominent approach in considerations of tobacco endgame strategies; it is endorsed by the American Medical Association, the British Medical Association, the US Food and Drug Administration (FDA) and the US Surgeon-General, and is also supported within the WHO Framework Convention on Tobacco Control (FCTC; see Chapter 19).76 A product standard for nicotine could be implemented through Articles 9 and 10 of the FCTC, which relate to the disclosure, testing, and regulation of the contents and emissions of tobacco products.18 The approach more broadly calls for research, government regulation, gradual reduction, consumer education, and increased availability of lower-risk options, in order to combat addiction and eliminate gateway risks.77

In its 2015 advisory note on a global nicotine reduction strategy, the WHO Study Group on Tobacco Product Regulation recommended that implementation of a nicotine-reduction policy should be supported by a comprehensive tobacco control program.11 In 2018, a joint meeting was held by the World Health Organization (WHO) and the Convention Secretariat of the FCTC to examine the potential effects of a regulatory policy to reduce nicotine in cigarettes to minimally addictive levels. It concluded that while some countries lack the capacity to implement such a policy, for those that can, it could substantially reduce the burden of tobacco use.18

An important consideration in the adoption of a nicotine reduction policy is ensuring that reduced nicotine content cigarettes are not perceived as less harmful, as some smokers erroneously believe that nicotine is one of the main causes of smoking-related disease.78-81 Research has shown that descriptions and marketing of reduced nicotine cigarettes can affect consumers’ perceptions,82, 83 with a systematic review finding that commercial features (i.e., advertising, packaging and descriptors from manufacturers) were generally related to favourable responses to the products, while public health features (such as warning labels) often offset these positive responses, though findings were more mixed.84 One study found that smokers perceived a cigarette described as containing very low nicotine content as having lower risks of health issues and various cancers compared with a cigarette with “average” nicotine.85 Evidence from focus groups in the US suggests that messaging should include that low nicotine content cigarettes are still harmful, but also that such products can make it easier for smokers to quit.86 Another US study found that when communicating a nicotine reduction standard to smokers, framing the information as cigarettes no longer being able to relieve cravings was the most effective for potentially promoting quitting.87

Along with harm misperceptions, researchers have also noted other potential unintended consequences, such as product manipulation37 and an illicit market.37, 50, 88 In order to minimise illicit trade, researchers have recommended tracking and tracing products and greater surveillance and enforcement,89 and in the context of enforcement, targeting manufacturing, distribution, and commercial sales, rather than individuals.37 Some have also argued that the risks of an illicit market are minimal, and do not outweigh the potential public health gains or justify a delay in implementing a reduced nicotine standard.90 It may also be important to consider extending the product standard to other combusted tobacco products,19, 91, 92 and to increase availability and access to cessation aids, support and education.37 Some smokers may benefit from concurrent use of nicotine replacement therapy to support quit attempts using very low nicotine cigarettes.93-95

Further, some researchers highlight that factors other than nicotine/addiction can also influence and reinforce smoking behaviours,96-98 and given that smoking reduced nicotine content cigarettes65 and low-level smoking (see Section 3.36) carry substantial health risks, regulatory efforts should be cognisant of these non-nicotine factors.96 For example, the relative prices of high nicotine versus low nicotine products may influence users’ choices.99, 100 Others have argued that the complexities of communicating a reduced tobacco product addictiveness policy to the public, combined with the potential for the tobacco industry to co-opt the messaging and for many other unintended consequences, may make such product standards ultimately ineffective. Instead, they suggest that it may be more beneficial for public health to focus on proposals to phase out retail sales of tobacco products entirely.101

12C.5 International approaches to reducing nicotine in cigarettes

Although a nicotine reduction standard for cigarettes has not been implemented anywhere in the world, several countries have taken some initial steps. Health Canada issued a tender in 2016 calling for research into the possibility of forcing tobacco companies to make their cigarettes less addictive,102 and issued another in 2018 requesting industry feedback regarding the feasibility and costs associated with procuring a supply of very low nicotine cigarettes.103 To date, it appears there has been no further progress on this strategy in Canada.

The US FDA included in its 2009 tobacco law the authority to reduce nicotine,104 and in 2018, issued an advance notice of proposed rulemaking to obtain information for consideration in developing a tobacco product standard to set the maximum nicotine level for cigarettes.105 In 2019, the FDA authorised the marketing of two variants of reduced nicotine content cigarettes manufactured by 22nd Century Group Inc.,  Moonlight and Moonlight Menthol.106 In 2021, the FDA further authorised 22nd Century Group to market two of its products – VLN King and VLN Menthol King – with certain reduced exposure claims regarding nicotine, including: “95% less nicotine”; “Helps reduce your nicotine consumption” and “...Greatly reduces your nicotine consumption.”107 As at late 2021, the FDA was reportedly still considering requiring tobacco companies to reduce the amount of nicotine in cigarettes to nonaddictive levels.108

Critics of the US proposal have argued that it may not be practicable within the confines of FDA law. Or, if it is, it may take many years to implement, and would require mandatory low nicotine content to succeed. They contend that resources would be better allocated to more pleasurable and likely less harmful forms of nicotine use, such as vaping and snus.76 Alternatively, others have suggested a combination of these strategies; that is, reducing the nicotine content of smoked tobacco products while allowing non-combustible recreational nicotine products to be sold.109-111 A review of legal arguments that the tobacco industry is likely to advance in response to the FDA implementing non-addictive nicotine levels concluded that the FDA stands on solid legal ground, and that there are strong arguments that it has the authority to implement such policy.112

In December 2021, the New Zealand Government released its Smokefree Aotearoa 2025 Action Plan, outlining its proposals for the next four years to meet its goal of a daily smoking prevalence of less than five percent for all population groups by 2025. One of the focus areas of the report is to reduce the addictiveness and appeal of smoked tobacco products, as “Reducing nicotine in smoked tobacco products to minimally addictive levels will help people to either quit or swap to a less harmful alternative.”  The Government has stated that in 2022 it will introduce an amendment Bill to allow only very low nicotine levels in smoked tobacco products for manufacture, importation, distribution, and sale in New Zealand, and that it will introduce product assurance systems to support compliance with these requirements.32 All Imperial Brands cigarette products sold in Australia are currently manufactured in New Zealand.113


Relevant news and research

For recent news items and research on this topic, click  here. ( Last updated March 2024)



1. Benowitz N. Pharmacologic aspects of cigarette smoking and nicotine addition. New England Journal of Medicine, 1988; 319(20):1318–30. Available from:

2. Zhou X, Nonnemaker J, Sherrill B, Gilsenan AW, Coste F, et al. Attempts to quit smoking and relapse: Factors associated with success or failure from the attempt cohort study. Addictive Behaviors, 2009; 34(4):365–73. Available from:

3. Gray RJ, Hoek J, and Edwards R. A qualitative analysis of 'informed choice' among young adult smokers. Tobacco Control, 2016; 25(1):46–51. Available from:

4. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, et al. Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiology, Biomarkers & Prevention, 2007; 16(11):2479–85. Available from:

5. Douglas CE. Taking aim at the bull's-eye: The nicotine in tobacco products. Tobacco Control, 1998; 7(3):215–8. Available from:

6. Kessler DA, Natanblut SL, Wilkenfeld JP, Lorraine CC, Mayl SL, et al. Nicotine addiction: A pediatric disease. J Pediatr, 1997; 130(4):518–24. Available from:

7. Davis RM, Douglas CE, and Beasley JK. The tobacco deposition and trial testimony archive (datta) project: Origins, aims, and methods. Tobacco Control, 2006; 15 Suppl 4(suppl 4):iv4–8. Available from:

8. Douglas C. A question of intent: A great American battle with a deadly industry. BMJ : British Medical Journal, 2001; 322(7294):1129–. Available from:

9. Benowitz NL and Henningfield JE. Establishing a nicotine threshold for addiction. The implications for tobacco regulation. New England Journal of Medicine, 1994; 331(2):123–5. Available from:

10.   Benowitz NL and Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. Tobacco Control, 2013; 22 Suppl 1(suppl 1):i14–7. Available from:

11.   World Health Organization. Advisory note: Global nicotine reduction strategy: Who study group on tobacco product regulation. 2015. Available from:

12.   World Health Organization. WHO study group on tobacco product regulation. Report on the scientific basis of tobacco product regulation: Seventh report of a who study group. Geneva: World Health Organization, 2019. Available from:

13.   Donny EC, Denlinger RL, Tidey JW, Koopmeiners JS, Benowitz NL, et al. Randomized trial of reduced-nicotine standards for cigarettes. New England Journal of Medicine, 2015; 373(14):1340–9. Available from:

14.   Perkins KA and Karelitz JL. Differences in acute reinforcement across reduced nicotine content cigarettes. Psychopharmacology (Berl), 2020; 237(6):1885–91. Available from:

15.   Higgins ST, Tidey JW, Sigmon SC, Heil SH, Gaalema DE, et al. Changes in cigarette consumption with reduced nicotine content cigarettes among smokers with psychiatric conditions or socioeconomic disadvantage: 3 randomized clinical trials. JAMA Netw Open, 2020; 3(10):e2019311. Available from:

16.   Perkins KA and Karelitz JL. A forced-choice procedure to assess the acute relative reinforcing effects of nicotine dose per se in humans. Nicotine & Tobacco Research, 2020; 22(10):1685–93. Available from:

17.   Perkins KA. Research on behavioral discrimination of nicotine may inform FDA policy on setting a maximum nicotine content in cigarettes. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S5–S12. Available from:

18.   Hatsukami DK, Xu D, and Ferris Wayne G. Regulatory approaches and implementation of minimally addictive combusted products. Nicotine & Tobacco Research, 2021. Available from:

19.   White CM, Pickworth WB, Sved AF, and Donny EC. Using product standards to render the most harmful tobacco products minimally addictive: Maximum nicotine level, non-nicotine constituents, and scope. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S13–S5. Available from:

20.   Kamens HM, Silva CP, Nye RT, Miller CN, Singh N, et al. Pharmacokinetic profile of Spectrum reduced nicotine cigarettes. Nicotine & Tobacco Research, 2020; 22(2):273–9. Available from:

21.   Havermans A, Pieper E, Henkler-Stephani F, and Talhout R. Feasibility of manufacturing tobacco with very low nicotine levels. Tobacco Regulatory Science, 2020; 6(6):405–15. Available from:

22.   Valleau WD. Breeding low-nicotine tobacco. Journal of Agricultural Research, 1949; 78:171–81. Available from:

23.   Li C, Teng W, Shi Q, and Zhang F. Multiple signals regulate nicotine synthesis in tobacco plant. Plant Signal Behav, 2007; 2(4):280–1. Available from:

24.   Ma H, Wang F, Wang W, Yin G, Zhang D, et al. Alternative splicing of basic chitinase gene pr3b in the low-nicotine mutants of nicotiana tabacum l. Cv. Burley 21. J Exp Bot, 2016; 67(19):5799–809. Available from:

25.   Hibi N, Higashiguchi S, Hashimoto T, and Yamada Y. Gene expression in tobacco low-nicotine mutants. Plant Cell, 1994; 6(5):723–35. Available from:

26.   Schachtsiek J and Stehle F. Nicotine-free, nontransgenic tobacco (nicotiana tabacum l.) edited by crispr-cas9. Plant Biotechnol J, 2019; 17(12):2228–30. Available from:

27.   Lin B, Yao Y, Wang Y, Chen L, Peng X, et al. Facile fabrication of a functional filter tip for highly efficient reduction of nicotine content in mainstream smoke. ACS Appl Mater Interfaces, 2021; 13(31):37638–44. Available from:

28.   22nd Century Group Inc. Our company.  2022. Available from:

29.   Apelberg BJ, Feirman SP, Salazar E, Corey CG, Ambrose BK, et al. Potential public health effects of reducing nicotine levels in cigarettes in the United States. New England Journal of Medicine, 2018; 378(18):1725–33. Available from:

30.   Tengs TO, Ahmad S, Savage JM, Moore R, and Gage E. The AMA proposal to mandate nicotine reduction in cigarettes: A simulation of the population health impacts. Preventive Medicine, 2005; 40(2):170–80. Available from:

31.   Levy DT, Cummings KM, Heckman BW, Li Y, Yuan Z, et al. The public health gains had cigarette companies chosen to sell very low nicotine cigarettes. Nicotine & Tobacco Research, 2021; 23(3):438–46. Available from:

32.   Ministry of Health. Smokefree Aotearoa 2025 action plan - Auahi Kore Aotearoa Mahere Rautaki 2025. Wellington: Ministry of Health, 2021. Available from:

33.   Wilson N, Hoek J, Nghiem N, Summers J, Grout L, et al. Modelling the impacts of tobacco denicotinisation on achieving the smokefree 2025 goal in Aotearoa New Zealand. New Zealand Medical Journal, 2022; 135(1548). Available from:

34.   Cassidy RN, Tidey JW, Cao Q, Colby SM, McClernon FJ, et al. Age moderates smokers' subjective response to very-low nicotine content cigarettes: Evidence from a randomized controlled trial. Nicotine & Tobacco Research, 2019; 21(7):962–9. Available from:

35.   Cassidy RN, Colby SM, Tidey JW, Jackson KM, Cioe PA, et al. Adolescent smokers' response to reducing the nicotine content of cigarettes: Acute effects on withdrawal symptoms and subjective evaluations. Drug and Alcohol Dependence, 2018; 188:153–60. Available from:

36.   Sweitzer MM, Pacek LR, Kozink RV, Locey E, Kollins SH, et al. Reactions to reduced nicotine content cigarettes in a sample of young adult, low-frequency smokers. Psychopharmacology (Berl), 2021; 238(9):2429–38. Available from:

37.   Donny EC and White CM. A review of the evidence on cigarettes with reduced addictiveness potential. Int J Drug Policy, 2022; 99:103436. Available from:

38.   Colby SM, Cassidy RN, Denlinger-Apte R, Smith TT, Pacek LR, et al. Anticipated effects of nicotine reduction on youth smoking initiation and maintenance. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S46–S8. Available from:

39.   Shiffman S, Scholl SM, and Mao JM. Very-low-nicotine-content cigarettes and dependence among non-daily smokers. Drug and Alcohol Dependence, 2019; 197:1–7. Available from:

40.   Klemperer EM, Hughes JR, Callas PW, Benner JA, and Morley NE. Effectiveness of switching to very low nicotine content cigarettes plus nicotine patch versus reducing daily cigarette consumption plus nicotine patch to decrease dependence: An exploratory randomized trial. Addiction, 2019; 114(9):1639–50. Available from:

41.   Smith TT, Koopmeiners JS, Tessier KM, Davis EM, Conklin CA, et al. Randomized trial of low-nicotine cigarettes and transdermal nicotine. American Journal of Preventive Medicine, 2019; 57(4):515–24. Available from:

42.   Shiffman S, Kurland BF, Scholl SM, and Mao JM. Nondaily smokers' changes in cigarette consumption with very low-nicotine-content cigarettes: A randomized double-blind clinical trial. JAMA Psychiatry, 2018; 75(10):995–1002. Available from:

43.   Benowitz NL, Nardone N, Dains KM, Hall SM, Stewart S, et al. Effect of reducing the nicotine content of cigarettes on cigarette smoking behavior and tobacco smoke toxicant exposure: 2-year follow up. Addiction, 2015; 110(10):1667–75. Available from:

44.   Dermody SS, McClernon FJ, Benowitz N, Luo X, Tidey JW, et al. Effects of reduced nicotine content cigarettes on individual withdrawal symptoms over time and during abstinence. Experimental and Clinical Psychopharmacology, 2018; 26(3):223–32. Available from:

45.   Hatsukami DK, Donny EC, Koopmeiners JS, and Benowitz NL. Compensatory smoking from gradual and immediate reduction in cigarette nicotine content. Cancer Epidemiology, Biomarkers & Prevention, 2015; 24(2):472–6. Available from:

46.   Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, et al. Reduced nicotine content cigarettes: Effects on toxicant exposure, dependence and cessation. Addiction, 2010; 105(2):343–55. Available from:

47.   Hatsukami DK, Heishman SJ, Vogel RI, Denlinger RL, Roper-Batker AN, et al. Dose-response effects of spectrum research cigarettes. Nicotine & Tobacco Research, 2013; 15(6):1113–21. Available from:

48.   Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, et al. Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiology, Biomarkers & Prevention, 2012; 21(5):761–9. Available from:

49.   Park EY, Park E, Jeong BY, Park J, Lee DH, et al. Comparison of smoking cessation rates of quitline users in Korea between smokers of ultra-low nicotine yield cigarettes and other types of cigarette: A prospective study. Addiction, 2020; 115(9):1745–53. Available from:

50.   Smith TT, Heckman BW, Tidey JW, Colby SM, and Cummings KM. Behavioral outcomes of nicotine reduction in current adult smokers. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S125–S7. Available from:

51.   Smith TT, Koopmeiners JS, White CM, Denlinger-Apte RL, Pacek LR, et al. The impact of exclusive use of very low nicotine cigarettes on compensatory smoking: An inpatient crossover clinical trial. Cancer Epidemiology, Biomarkers & Prevention, 2020; 29(4):880–6. Available from:

52.   Smith TT, Koopmeiners JS, Hatsukami DK, Tessier KM, Benowitz NL, et al. Mouth-level nicotine intake estimates from discarded filter butts to examine compensatory smoking in low nicotine cigarettes. Cancer Epidemiology, Biomarkers & Prevention, 2020; 29(3):643–9. Available from:

53.   Denlinger-Apte RL, Donny EC, Lindgren BR, Rubin N, Goodwin C, et al. Smoking topography characteristics during a 6-week trial of very low nicotine content cigarettes in smokers with serious mental illness. Nicotine & Tobacco Research, 2020; 22(8):1414–8. Available from:

54.   Benowitz NL, Donny EC, Edwards KC, Hatsukami D, and Smith TT. The role of compensation in nicotine reduction. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S16–S8. Available from:

55.   Shiffman S, Mao JM, Kurland BF, and Scholl SM. Do non-daily smokers compensate for reduced cigarette consumption when smoking very-low-nicotine-content cigarettes? Psychopharmacology (Berl), 2018; 235(12):3435–41. Available from:

56.   Carroll DM, Lindgren BR, Dermody SS, Denlinger-Apte R, Egbert A, et al. Impact of nicotine reduction in cigarettes on smoking behavior and exposure: Are there differences by race/ethnicity, educational attainment, or gender? Drug and Alcohol Dependence, 2021; 225:108756. Available from:

57.   Hatsukami DK, Luo X, Jensen JA, al'Absi M, Allen SS, et al. Effect of immediate vs gradual reduction in nicotine content of cigarettes on biomarkers of smoke exposure: A randomized clinical trial. Journal of the American Medical Association, 2018; 320(9):880–91. Available from:

58.   Smith TT, Donny EC, Luo X, Allen AM, Carroll DM, et al. The impact of gradual and immediate nicotine reduction on subjective cigarette ratings. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S73–S80. Available from:

59.   Denlinger-Apte RL, White CM, Donny EC, Hatsukami DK, Benowitz NL, et al. "I actually finally feel like the cigarettes aren't controlling me." - interviews with participants smoking very low nicotine content cigarettes during a residential study. Drug and Alcohol Dependence, 2021; 219:108465. Available from:

60.   Denlinger-Apte RL, Koopmeiners JS, Tidey JW, Luo X, Smith TT, et al. Support for a nicotine reduction policy among participants enrolled in a 20-week trial of very low nicotine content cigarettes. Addictive Behaviors, 2021; 114:106727. Available from:

61.   Ali FRM, Al-Shawaf M, Wang TW, and King BA. U.S. Adults' attitudes toward lowering nicotine levels in cigarettes. American Journal of Preventive Medicine, 2019; 57(3):403–7. Available from:

62.   Denlinger-Apte RL, Tidey JW, Koopmeiners JS, Hatsukami DK, Smith TT, et al. Correlates of support for a nicotine-reduction policy in smokers with 6-week exposure to very low nicotine cigarettes. Tobacco Control, 2019; 28(3):352–5. Available from:

63.   Nighbor TD, Klemperer EM, Hughes JR, Reed EN, Simone SJ, et al. Both reducing cigarettes per day and transitioning to very low-nicotine-content cigarettes decreases demand for usual-brand cigarettes. Experimental and Clinical Psychopharmacology, 2021; 29(6):587–92. Available from:

64.   Robinson JD, Kypriotakis G, Al'absi M, Denlinger-Apte RL, Drobes DJ, et al. Very low nicotine content cigarettes disrupt the feedback loop of affective states and smoking behavior. Nicotine & Tobacco Research, 2020; 22(8):1294–300. Available from:

65.   Hatsukami DK, Luo X, Heskin AK, Tang MK, Carmella SG, et al. Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological effects. Addiction, 2019; 114(10):1824–33. Available from:

66.   Oliver AC, DeSarno M, Irvin CG, Kaminsky D, Tidey JW, et al. Effects of reduced nicotine content cigarettes on fractional exhaled nitric oxide and self-reported respiratory health outcomes among smokers with psychiatric conditions or socioeconomic disadvantage. Nicotine & Tobacco Research, 2022; 24(1):135–40. Available from:

67.   Gaalema DE, Tidey JW, Davis DR, Sigmon SC, Heil SH, et al. Potential moderating effects of psychiatric diagnosis and symptom severity on subjective and behavioral responses to reduced nicotine content cigarettes. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S29–S37. Available from:

68.   Higgins ST, DeSarno M, Bunn JY, Gaalema DE, Leventhal AM, et al. Cumulative vulnerabilities as a potential moderator of response to reduced nicotine content cigarettes. Preventive Medicine, 2021; 152(Pt 2):106714. Available from:

69.   Cassidy RN, Tidey JW, Cao Q, Colby SM, McClernon FJ, et al. Responses to gradual and immediate reduction of nicotine in cigarettes in young versus older adult smokers. Nicotine & Tobacco Research, 2021; 23(9):1559–66. Available from:

70.   Davis DR, Parker MA, Villanti AC, Streck JM, Priest JS, et al. Examining age as a potential moderator of response to reduced nicotine content cigarettes in vulnerable populations. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S49–S55. Available from:

71.   Streck JM, Davis DR, Pang RD, Sigmon SC, Bunn JY, et al. Potential moderating effects of sex/gender on the acute relative reinforcing and subjective effects of reduced nicotine content cigarettes in vulnerable populations. Nicotine & Tobacco Research, 2020; 22(6):878–84. Available from:

72.   Heil SH, Bergeria CL, Lee DC, Bunn JY, Harfmann RF, et al. Abuse liability of cigarettes with very low nicotine content in pregnant cigarette smokers. Preventive Medicine, 2020; 140:106227. Available from:

73.   Streck JM, Bergeria CL, Parker MA, Davis DR, DeSarno M, et al. Response to reduced nicotine content cigarettes among smokers with chronic health conditions. Preventive Medicine Reports, 2018; 12:321–9. Available from:

74.   Dermody SS, Tessier KM, Meier E, al'Absi M, Denlinger-Apte RL, et al. An evaluation of potential unintended consequences of a nicotine product standard: A focus on drinking history and outcomes. Nicotine & Tobacco Research, 2021; 23(7):1168–75. Available from:

75.   Schlagintweit HE, Tyndale RF, and Hendershot CS. Acute effects of a very low nicotine content cigarette on laboratory smoking lapse: Impacts of nicotine metabolism and nicotine dependence. Addict Biol, 2021; 26(3):e12930. Available from:

76.   Kozlowski LT. Prospects for a nicotine-reduction strategy in the cigarette endgame: Alternative tobacco harm reduction scenarios. Int J Drug Policy, 2015; 26(6):543–7. Available from:

77.   Benowitz NL and Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. Tobacco Control, 2013; 22(suppl 1):i14–i7. Available from:

78.   King B, Borland R, Yong HH, Gartner C, Hammond D, et al. Understandings of the component causes of harm from cigarette smoking in Australia. Drug Alcohol Rev, 2019; 38(7):807–17. Available from:

79.   Denlinger-Apte RL, Cassidy RN, Colby SM, Sokolovsky AW, and Tidey JW. Effects of cigarette nicotine content and menthol preference on perceived health risks, subjective ratings, and carbon monoxide exposure among adolescent smokers. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S56–S62. Available from:

80.   Denlinger-Apte RL, Pacek LR, Ross JC, Bansal-Travers M, Donny EC, et al. Risk perceptions of low nicotine cigarettes and alternative nicotine products across priority smoking populations. International Journal of Environmental Research and Public Health, 2021; 18(10). Available from:

81.   Villanti AC, Byron MJ, Mercincavage M, and Pacek LR. Misperceptions of nicotine and nicotine reduction: The importance of public education to maximize the benefits of a nicotine reduction standard. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S88–S90. Available from:

82.   Johnson AC, Mays D, Villanti AC, Niaura RS, Rehberg K, et al. Marketing influences on perceptions of reduced nicotine content cigarettes. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S117–S24. Available from:

83.   Byron MJ, Hall MG, King JL, Ribisl KM, and Brewer NT. Reducing nicotine without misleading the public: Descriptions of cigarette nicotine level and accuracy of perceptions about nicotine content, addictiveness, and risk. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S101–S7. Available from:

84.   Johnson AC, Mercincavage M, Souprountchouk V, Rogelberg S, Sidhu AK, et al. Responses to reduced nicotine cigarette marketing features: A systematic review. Tobacco Control, 2021. Available from:

85.   Denlinger-Apte RL, Joel DL, Strasser AA, and Donny EC. Low nicotine content descriptors reduce perceived health risks and positive cigarette ratings in participants using very low nicotine content cigarettes. Nicotine & Tobacco Research, 2017; 19(10):1149–54. Available from:

86.   Duong HT, Loud EE, Thrasher JF, Henderson KC, Ashley DL, et al. 'It brings light to what you really put into your body': A focus group study of reactions to messages about nicotine reduction in cigarettes. Tobacco Control, 2021. Available from:

87.   Popova L, Owusu D, Nyman AL, Weaver SR, Yang B, et al. Effects of framing nicotine reduction in cigarettes on anticipated tobacco product use intentions and risk perceptions among US adult smokers. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S108–S16. Available from:

88.   Hall MG, Byron JM, Brewer NT, Noar SM, and Ribisl KM. Interest in illicit purchase of cigarettes under a very low nicotine content product standard. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S128–S32. Available from:

89.   Ribisl KM, Hatsukami DK, Huang J, Williams RS, and Donny EC. Strategies to reduce illicit trade of regular nicotine tobacco products after introduction of a low-nicotine tobacco product standard. American Journal of Public Health, 2019; 109(7):1007–14. Available from:

90.   Lindblom EN. Illicit trade poses no threat to an FDA rule to minimize nicotine in smoked tobacco products. American Journal of Public Health, 2019; 109(7):960–1. Available from:

91.   Patel M, Cuccia AF, Czaplicki L, Donovan EM, Simard B, et al. Smokers' behavioral intentions in response to a low-nicotine cigarette policy. Drug and Alcohol Dependence, 2019; 205:107645. Available from:

92.   Byron MJ, Strasser AA, and Delnevo CD. Little and filtered cigars meet the legal definition of cigarettes and should be included in nicotine reduction regulation. Tobacco Control, 2019; 28(3):350–1. Available from:

93.   Krebs NM, Zhu J, Wasserman E, Kuprewicz R, Martinez DJ, et al. Switching to progressively reduced nicotine content cigarettes in smokers with low socioeconomic status: A double-blind randomized clinical trial. Nicotine & Tobacco Research, 2021; 23(6):992–1001. Available from:

94.   Tidey JW, Colby SM, Denlinger-Apte RL, Goodwin C, Cioe PA, et al. Effects of 6-week use of very low nicotine content cigarettes in smokers with serious mental illness. Nicotine & Tobacco Research, 2019; 21(Suppl 1):S38–S45. Available from:

95.   Reed GL, Colby SM, Sokolovsky AW, Snell LM, DeAtley T, et al. Predicting non-adherence with very low nicotine content cigarettes among adults with serious mental illness who smoke. Nicotine & Tobacco Research, 2021. Available from:

96.   White CM, Hatsukami DK, and Donny EC. Reducing the relative value of cigarettes: Considerations for nicotine and non-nicotine factors. Neuropharmacology, 2020; 175:108200. Available from:

97.   Lin W, Krebs NM, Zhu J, Foulds J, Horn K, et al. Comparison between gradual reduced nicotine content and usual nicotine content groups on subjective cigarette ratings in a randomized double-blind trial. International Journal of Environmental Research and Public Health, 2020; 17(19). Available from:

98.   Kaplan BA, Koffarnus MN, Franck CT, and Bickel WK. Effects of reduced-nicotine cigarettes across regulatory environments in the experimental tobacco marketplace: A randomized trial. Nicotine & Tobacco Research, 2021; 23(7):1123–32. Available from:

99.   Davis DR, DeSarno MJ, Bergeria CL, Streck JM, Tidey JW, et al. Examining effects of unit price on preference for reduced nicotine content cigarettes and smoking rate. Preventive Medicine, 2019; 128:105823. Available from:

100. Branstetter SA, Nye R, Sipko JJ, and Muscat JE. The effect of price on the consumption of reduced nicotine cigarettes. Nicotine & Tobacco Research, 2019; 21(7):955–61. Available from:

101. Bialous S and Freeman B. Communication challenges of a tobacco addictiveness reduction policy. Tobacco Induced Diseases, 2021; 19:38. Available from:

102. Government of Canada. Health benefits modeling, expert elicitation and analysis relating to a product standard (1000174109). 2016. Available from:

103. Government of Canada. Request for information regarding availability, costing, and storage of Canadian very low nicotine content Virginia flue-cured cigarettes (1000198655). 2018. Available from:

104. United States Code. Family Smoking Prevention and Tobacco Control Act. In stat 1776 United States. 2009. Available from:

105. Federal Register. Tobacco product standard for nicotine level of combusted cigarettes. Proposed Rule, U.S. Department of Health and Human Services,  2018. Available from:

106. Food and Drug Administration. FDA permits sale of two new reduced nicotine cigarettes through premarket tobacco product application pathway.  2019. Available from:

107. Food and Drug Administration. FDA authorizes marketing of tobacco products that help reduce exposure to and consumption of nicotine for smokers who use them.  2021. Available from:

108. Roubein R. Biden's FDA pick faces questions about his tobacco response. The Washington Post, 2021. Available from:

109. Hall W and Gartner C. Supping with the devil? The role of law in promoting tobacco harm reduction using low nitrosamine smokeless tobacco products. Public Health, 2009; 123(3):287–91. Available from:

110. Benowitz NL, Donny EC, and Hatsukami DK. Reduced nicotine content cigarettes, e-cigarettes and the cigarette end game. Addiction, 2017; 112(1):6–7. Available from:

111. Smith TT, Hatsukami DK, Benowitz NL, Colby SM, McClernon FJ, et al. Whether to push or pull? Nicotine reduction and non-combusted alternatives - two strategies for reducing smoking and improving public health. Preventive Medicine, 2018; 117:8–14. Available from:

112. Berman ML, Zettler PJ, and Ashley DL. Anticipating industry arguments: The US Food and Drug Administration's authority to reduce nicotine levels in cigarettes. Public Health Rep, 2018; 133(4):502–6. Available from:

113. Cancer Council Victoria. Product library. Melbourne, Australia January 2022.