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Abstract
Large reductions in nicotine content could dramatically reduce reinforcement from and dependence on cigarettes. In this article, we summarise the potential benefits of reducing nicotine in combusted tobacco and address some of the common concerns. We focus specifically on New Zealand because it may be ideally situated to implement such a policy. The available data suggest that, in current smokers, very low nicotine content (VLNC) cigarettes decrease nicotine exposure, decrease cigarette dependence, reduce the number of cigarettes smoked per day and increase the likelihood of contemplating, making and succeeding at a quit attempt. New smokers would almost certainly be exposed to far less nicotine as a result of smoking VLNC cigarettes and, consequently, would probably be less likely to become chronic, dependent, smokers. Many of the concerns about reducing nicotine including compensatory smoking, an exacerbation of psychiatric symptoms, the perception that VLNC cigarettes are less harmful, and the potential for a black market are either not supported by the available data, likely mitigated by other factors including the availability of nicotine-containing e-cigarettes, or unlikely to offset the potential benefit to public health. Although not all concerns have been addressed or can be a priori, the magnitude of the potential benefits and the growing evidence of relatively few potential harms should make nicotine reduction one of the centrepieces for discussion of how to rapidly advance tobacco control. Policies that aim to render the most toxic tobacco products less addictive could help New Zealand attain their goal of becoming smokefree by 2025.
- Addiction
- End game
- Harm Reduction
- Nicotine
- Public policy
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Objective
To address the potential benefits, potential harms and common concerns related to reducing the nicotine content of combusted tobacco products in New Zealand and generate discussion as to whether policies targeting nicotine content would likely facilitate reaching the goal of becoming smokefree by 2025.
Introduction
Decades of research suggest that nicotine drives the use of cigarettes and other forms of combusted tobacco. Large reductions in nicotine content could dramatically reduce reinforcement from and dependence on cigarettes.1 In this article, we summarise the potential benefits of reducing nicotine in combusted tobacco and address some of the common concerns. The review is not exhaustive; it is intended to provide an overview of the current evidence in order to generate and guide discussion about the potential impact of substantially reducing the nicotine content of combusted tobacco products.
We focus on New Zealand for several reasons. First, it has a clearly defined goal of becoming smokefree (<5% prevalence) by 2025. Second, it has well-developed tobacco control programmes, including infrastructure for supporting quit attempts. Third, the New Zealand government is currently reviewing policies related to a recently announced intention to allow the sale of nicotine-containing e-cigarettes.2 These products may prove to be viable alternatives to reduced nicotine cigarettes. Furthermore, the policy discussions provide a context for debate about a more comprehensive and integrated nicotine policy aimed at decoupling the link between nicotine and the deadly by-products of combusted tobacco.2 ,3 Fourth, policies that reduce nicotine have gained considerable support among many local tobacco control advocates and are acceptable to most smokers and non-smokers, including populations with high smoking prevalence (ie, Māori, Pacific Islanders). Fifth, advertising bans enable control of messaging regarding the impact of reducing nicotine and the continued harms associated with combusted tobacco. Finally, New Zealand is an island nation with likely reduced risk of contraband. These features are consistent with recent recommendations by the WHO Study Group on Tobacco Product Regulation regarding nicotine reduction3 and may provide a unique opportunity for New Zealand to implement this novel approach to reducing combusted tobacco use.
Evidence-based potential benefits of reducing nicotine in cigarettes
The concept of reducing nicotine content in tobacco to render tobacco products less addictive is decades old,1 but clinical trials evaluating the impact of extended use of very low nicotine content (VLNC) cigarettes have emerged recently. Compared to control cigarettes with 15.8 mg nicotine per gram of tobacco, use of cigarettes with only 0.4 mg/g nicotine by smokers who are not currently interested in quitting leads to decreased nicotine exposure,4–6 decreased cigarette dependence,5 ,7 fewer cigarettes smoked per day5 ,8 and increased likelihood of contemplating or making a quit attempt.5 ,7 Standardised effect sizes comparing 0.4–15.8 mg/g nicotine are moderate (Fagerström Test for Nicotine Dependence: 0.65) to large (cigarettes per day: 0.79; urinary total nicotine equivalents: 0.82) after 6 weeks of use5 (EC Donny, 2016, unpublished observations). Likewise, in smokers currently interested in quitting, the use of VLNC cigarettes prior to a quit attempt leads to decreased nicotine exposure,9 ,10 decreased cigarette dependence9 and fewer cigarettes per day.9 ,10 Furthermore, use of VLNC cigarettes prior to making a quit attempt has been shown to decrease the likelihood of relapse relative to use of control cigarettes9 with mixed evidence as to whether VLNC cigarettes facilitate abstinence over and above nicotine replacement therapy.10 ,11 Finally, ex-smokers who recently quit are less likely to relapse if they use VLNC cigarettes when they experience a strong urge to smoke.12 It is worth noting that in each of the cessation studies, participants were attempting to refrain from smoking their usual brand cigarettes that contain much higher levels of nicotine. It is unclear what relapse would look like if only VLNC cigarettes were available, but data indicate reduced craving when smokers who have been using VLNC cigarettes for 6 weeks refrain from smoking.5 In sum, these data are consistent with the long-established consensus that nicotine is the primary constituent in tobacco that drives smoking behaviour.13
VLNC cigarettes would not be safer than normal cigarettes. Although some toxicants may change as a result of nicotine reduction (eg, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), most harmful and potentially harmful constituents are similar to commercial or reference cigarettes,14 ,15 resulting in largely unchanged urinary biomarkers of toxicant exposure following short-term use (ie, when cigarettes per day remain relatively stable).15–18 Longer studies that have resulted in fewer cigarettes per day have observed parallel decreases in urinary biomarkers of toxicant exposure,9 highlighting how reduction in harm is secondary to changes in behaviour.19
One might assume that reducing nicotine would also render cigarettes less reinforcing to adolescents who start smoking. New smokers would almost certainly be exposed to less nicotine as a result of their smoking6 and, consequently, would probably be less likely to continue to smoke and develop dependence.3 Although conclusive experimental data from nicotine-naïve adolescents cannot be obtained for ethical reasons, animal data are consistent with this assumption; adolescent rats given access to doses of nicotine that fail to maintain self-administration in adults are less likely to acquire nicotine self-administration.20
Common questions
Many questions about VLNC cigarettes have been raised by scientists, public health advocates and policymakers.21–32 We address the most common ones in turn.
Would mandated nicotine reduction result in clinically significant changes in smoking?
The primary way in which VLNC cigarettes would reduce harm is by facilitating smoking cessation. Current data suggest that cessation would increase by increasing the number of smokers attempting to quit5 and increasing the probability that a given quit attempt is successful.9 ,12 How these findings translate to the potential population impact is difficult to judge because participants in clinical trials can easily access non-study cigarettes high in nicotine, generally do not use alternative nicotine delivery systems (ANDS) either at baseline or as part of the protocol, and know the changes in their cigarettes are temporary. Cessation-focused research is ongoing (eg, NCT#02796391); however, it is hard to imagine that greatly reducing exposure to the primary constituent of tobacco that sustains reinforcement from and dependence on cigarettes will not lead to substantially more smoking cessation. If responses to a hypothetical scenario from participants who used VLNC cigarettes for 6 weeks are any indication, the impact could be enormous. In our recent trial,5 approximately half of the participants indicated that they would stop smoking within a year if their assigned VLNC cigarette was the only type of cigarette available to purchase (Donny, unpublished observations).
Is it technologically feasible to manufacture VLNC cigarettes?
Yes, it has been possible for decades. Methods include degradation, extraction and genetic engineering.3 In fact, several low nicotine content products have been manufactured and sold on the market in the past, alongside normal nicotine content cigarettes (eg, Next and Quest cigarettes), although their market share has been limited. VLNC cigarettes are currently being marketed in Europe and Australia under the brand name Magic. Investigational VLNC cigarettes are available through the US National Institute on Drug Abuse under the brand name Spectrum. Spectrum cigarettes use a similar proprietary genetic engineering and plant breeding method of reducing nicotine as Quest and Magic cigarettes. The impact and viability of other methods of reducing nicotine is largely unknown, although some methods may be more acceptable to consumers than others.32
How large would the reduction in nicotine need to be?
The nicotine content of the 22 most popular factory manufactured and roll-your-own cigarettes in New Zealand ranges from 8 to 18 mg nicotine per gram of tobacco.33 On the basis of current data, the optimal level for reducing addictiveness would be ≤0.4 mg per gram of tobacco,3 ,5 a 95–98% reduction in nicotine content relative to what is currently on the market.
Do smokers compensate by smoking more?
Although smokers may attempt to compensate when they first try VLNC cigarettes, numerous studies have shown that most smokers do not compensate after the first few cigarettes5 ,34 ,35 and that biomarkers of smoke exposure do not increase when participants are switched to VLNC cigarettes.4 ,5 ,8 ,9 ,16 ,17 One limitation of clinical trials suggesting little or no compensation is that smokers could easily purchase normal nicotine cigarettes, although an inpatient study in which participants could only use VLNC cigarettes also demonstrated a reduction in smoke exposure.8 Furthermore, analysis of VLNC cigarette butts suggests that participants are less likely to smoke intensely than participants using higher nicotine content cigarettes.18 The absence of lasting increases in the number of cigarettes smoked, smoking intensity, and biomarkers of smoke exposure is in contrast to well-described changes that occur when smokers are switched to light cigarettes (ie, in which machine-estimated nicotine yield is reduced through ventilation, not through reduced nicotine content).36 This difference is likely related to the fact that compensatory smoking can effectively maintain a similar level of nicotine exposure per cigarette when nicotine yield is manipulated by altering ventilation, but changes in smoking behaviour cannot maintain nicotine exposure when the nicotine content of cigarettes is greatly reduced. Nevertheless, smoking behaviour and toxicant exposure should be closely monitored if nicotine content is reduced.
Do smokers perceive low nicotine cigarettes as safer?
Smokers often misattribute the harm from smoking to nicotine. It remains important to convey that all cigarettes are extremely harmful, including low nicotine cigarettes. Nevertheless, smoking is reduced by VLNC cigarettes despite the perception of reduced harm5 (EC Donny, 2016, unpublished observations). Therefore, reduced perceived harm is best viewed as a potential unintended consequence that needs to be mitigated with effective public health media messaging; it is unlikely to outweigh the potential benefits of nicotine reduction.
Would individuals with psychiatric disorders suffer as a result of mandated reductions?
VLNC cigarettes are unlikely to pose a significant threat to smokers with psychiatric disorders.37 ,38 Smokers with psychiatric disorders commonly quit smoking with standard treatments and experience little deterioration or even improvements in their psychiatric symptoms.37 ,38 Initial studies of smokers with elevated baseline symptoms of depression (Center for Epidemiological Studies—Depression Scale, CES-D, ≥16) or schizophrenia suggest that use of VLNC cigarettes does not exacerbate their symptoms.39 ,40 Furthermore, smokers with psychiatric disorders would likely experience similar benefits related to their cigarette use (ie, reduced smoking, reduced dependence and increased quitting). For example, participants with elevated baseline symptoms of depression (CES-D ≥16) displayed similar reductions in nicotine exposure, cigarettes per day and dependence as participants with fewer symptoms of depression.39 Nevertheless, given the potential concerns the use of VLNC cigarettes might present in smokers with psychiatric comorbidities,21 ,37 research is underway and likely to provide more definitive evidence within the next few years, including studies of smokers with affective disorders, schizophrenia, attention deficit hyperactivity disorder and current opioid abuse (see online supplementary materials). If enacted, the impact of a policy reducing the nicotine content of cigarettes can be closely monitored, particularly in comorbid populations, through postregulation surveillance.
Supplemental material
How acceptable is this approach to the public, including to current smokers?
In a population-based survey of New Zealanders, 81% indicated they agree with the statement, “The nicotine content of cigarettes should be reduced to very low levels so that they are less addictive”, including 63% of current smokers, 73% of Māori and 87% of Pacific Islanders.41 Unpublished observations from the study by Donny et al5 suggest that even when smokers experienced VLNC cigarettes for 6 weeks (and judged their experimental cigarettes to be low or very low in nicotine), they were approximately twice as likely to support than oppose regulated reductions in nicotine content (EC Donny, 2016).
What would the impact be on Māori?
In a large New Zealand trial of VLNC cigarettes for smoking cessation, 24% of the sample identified as Māori. Quitting behaviour with use of VLNC cigarettes combined with nicotine replacement therapy and behavioural support was the same irrespective of ethnicity.12 The Māori Affairs Committee suggested in its 2010 report that “Nicotine, the addictive substance in tobacco, should be rigorously regulated” and that “Regulating nicotine content should be a priority.”42
Should VLNC cigarettes be introduced alongside normal cigarettes?
If available at the same price, VLNC cigarettes are unlikely to be widely used.7 If available at a significantly lower price, VLNC cigarettes could substitute for normal cigarettes. One small trial (n=33) in New Zealand found that a price differential of ∼NZ$15 between usual brand and VLNC cigarettes led to reduced nicotine exposure and dependence in the group with access to VLNC cigarettes, but the total number of cigarettes (VLNC and usual brand) smoked remained the same as baseline.7 On the basis of these data, price-based approaches in which low and high nicotine cigarettes are concurrently available would likely require large differences in price to motivate product switching and reduce dependence.43 Differential taxation may be a useful first step towards a mandated reduction of nicotine content in all combusted tobacco to allow product development, familiarise smokers with VLNC cigarettes and begin to reduce nicotine exposure from smoking. Ultimately, the greatest public health benefit would be achieved if no high nicotine cigarettes were on the market.
Why not just ban all cigarettes?
Banning cigarettes may be more likely to lead to black markets, present significant legal/trade barriers and be less likely to be supported by smokers and opponents of government interference.22 ,24 ,25 ,41 ,44 ,45
Does nicotine reduction amount to prohibition?
The objective of reducing nicotine in cigarettes is to reduce the prevalence of smoking, not to prohibit nicotine use. Indeed, the availability of alternative sources of nicotine is consistent with this approach46 and may make reducing nicotine in combusted products more acceptable to the individual user, the public and the policymaker. Others have argued that nicotine reduction amounts to prohibition of conventional cigarettes.22 However, smokers use VLNC cigarettes even when no other products are available,5 ,8 although they may be less likely to persist in their use the over time (see above). Use of the term ‘prohibition’ to refer to a policy approach that targets the addictiveness of a specific class of products, and not the drug itself, is unfortunate as it leverages fear of the social consequences of alcohol prohibition. Cigarettes also hold a very different place in society than alcohol did in the early 1900s. Most cigarettes are consumed by dependent smokers who regret use and want to quit, not by recreational, non-dependent users.47
Would New Zealand be at risk for litigation by the tobacco industry?
Possibly, although unlike a ban, combusted tobacco products could still be sold in New Zealand. Standards for nicotine content are consistent with Article 9 of the WHO Framework Convention on Tobacco Control, of which New Zealand is a signatory. Furthermore, challenges based on trade agreements may be mitigated by the sale of alternative products (eg, e-cigarettes, nicotine replacement therapy), some of which are also manufactured by the tobacco industry.
Would there be a black market for normal nicotine content cigarettes?
It is likely that normal nicotine content black market cigarettes would become available, although the size, nature and harms of the black market are difficult to predict and would likely be related to how the policy is implemented, the resources dedicated to enforcement and the availability of alternative nicotine-containing products.44
Would smokers manipulate VLNC cigarettes?
Smokers could try to add nicotine to their cigarettes. For example, they could take nicotine e-liquids and drip it on manufactured cigarettes or soak their roll-your-own tobacco in it. Whether adding nicotine to VLNC cigarettes would yield an appealing and acceptable product is unknown as is the degree to which a manipulated VLNC cigarette would be preferred over ANDS. In sum, the extent of these practices (or other manipulation behaviours) is difficult to predict and should be monitored if a nicotine reduction strategy was to be implemented.
Might people continue to smoke for reasons other than nicotine?
Yes. Nicotine reduction is not intended to address all the reasons people smoke, but instead targets the neuropharmacological effects of combusted tobacco that are widely believed to be responsible for dependence. Although some other constituents of tobacco are psychoactive, current evidence from animal studies suggests that these other constituents, in the doses found in tobacco, would have little impact on behaviour either alone or in combination with low doses of nicotine.48 One non-nicotine effect of tobacco smoke—inhibition of monoamine oxidase—may increase sensitivity to the reinforcing effects of low doses of nicotine, but this effect does not appear to be sufficient to maintain rat self-administration if nicotine is adequately reduced.49 Furthermore, the observed decreases in cigarette use and dependence occurred in participants who were presumably exposed to most other non-nicotine tobacco constituents (note: VLNC cigarettes are generally similar to normal nicotine content cigarettes but have reduced levels of some alkaloids structurally related to nicotine).5 It is possible that industry could add other constituents to try to enhance the addictive potential of reduced nicotine combusted tobacco products. Disclosure of significant changes in product design and surveillance of patterns of use and dependence would be important components of any nicotine reduction policy.
What would be the impact on roll-your-own tobacco users?
Evidence from the large New Zealand trial of VLNC cigarettes indicates that quitting behaviour with use of VLNC cigarettes is the same, irrespective of whether participants used roll-your-tobacco only, or factory-made cigarettes only at baseline.12 VLNC loose tobacco can be made using the same processes as outlined above.
Conclusions
Reducing nicotine content as a means of reducing the abuse liability of combustible tobacco could have dramatic effects on public health. One early model estimated that the prevalence of smoking in the US would decline from 23% to 5%.19 Updated models are needed; however, even if the actual benefits are a fraction of that estimate, the impact on public health could be enormous. Consequently, we urge discussion of policies that would ultimately render the most toxic tobacco products less addictive. In light of the available data, we submit the following potential approach as a starting point to initiate widespread discussion of a policy targeting the nicotine content of all combusted tobacco.
Establish the explicit authority to mandate a reduction of nicotine (and related alkaloids) for all combusted tobacco products as part of a comprehensive tobacco control programme.50 The policy changes currently under consideration for ANDS will need to address concerns about ANDS acting as a gateway to smoking, dual use of ANDS and combusted tobacco and ANDS fostering renormalisation of smoking-like behaviours. Reducing nicotine in combusted tobacco would mitigate these concerns, decreasing the probability that users of ANDS will start or continue to smoke. Other concerns about ANDS themselves will also need to be addressed (eg, potential to cause some harm, to expose adolescents to nicotine and to lead to addiction). Consequently, the regulation of ANDS should focus on minimising toxicity, potential harm and youth access while allowing them to serve as viable alternatives to VLNC cigarettes, alongside widely available medicinal nicotine, for adults who choose to continue to use nicotine.46
Establish a target date for reducing the nicotine content of all combusted products. This date would allow for the collection and evaluation of additional data on VLNC cigarettes (see online supplementary material) and the evaluation of the impact of ANDS on combustible product use. If ANDS fail to adequately reduce smoking prevalence,51 ,52 standards for the nicotine content of cigarettes could be introduced with minimal delay.
Encourage the introduction of VLNC cigarettes that have ≤0.4 mg of nicotine content per gram of tobacco in New Zealand. Regulators should ensure appropriate warning labels (eg, product is not less harmful but may be less addictive) and consider a two-tiered tax system that favours VLNC over conventional cigarettes.33 ,43
Implement public messaging to explain the change in tobacco products including the introduction of nicotine-containing e-cigarettes and the long-term commitment to phase out tobacco products that are highly addictive and highly toxic.
If possible, identify early adopter communities who are motivated to implement a mandated nicotine reduction policy and monitor the impact of this implementation. Surveillance of such a community would provide the best estimate of the likely benefits and harms of regulatory action at the national level with important implications internationally.
Some will question whether this discussion is premature, pointing to the need for more data. No less than 15 clinical trials are underway testing the impact of nicotine reduction in smokers from many different segments of the population (see online supplementary material). Waiting for the results of these trials before seriously discussing a policy that is rooted in decades of research demonstrating the central role of nicotine in cigarette addiction could delay potential action and ultimately lead to a failure in efforts to more rapidly improve public health. Many have argued that alternative products could lead to the end of combusted tobacco. We agree that there is an urgent need to consider the potential positive impact of ANDS, but caution against putting all eggs in this basket. To date, many smokers have not tried ANDS or have, but do not find them to be an acceptable substitute for current, high nicotine, cigarettes.51 Consequently, the ultimate population impact of ANDS on smoking cessation may be smaller than expected.52 This may change with new product development and changes in public perception. However, whether the emergence of e-cigarettes and other ANDS is, by itself, enough to dramatically reduce combusted product use is unclear. Policymakers should consider what additional measures should be in place and if a more comprehensive policy that would expedite the transition away from combusted tobacco product use is necessary to achieve their policy objective of a ‘reduction of harm from tobacco smoking’.2 ,46 ,50
The merits of this specific approach should be discussed, and components may need to be revised based on the review of current and future data. Nevertheless, the fundamental goal of rendering the most toxic tobacco products less addictive deserves to be one of the centrepieces of policy debates about how to reduce the harms associated with combusted tobacco use. Nicotine reduction, particularly if embedded in other proposed approaches (eg, making nicotine-containing e-cigarettes available), may represent a viable path to achieving New Zealand's goal of becoming smokefree by 2025.
What this paper adds
We evaluated the opportunity for New Zealand to reduce the nicotine content of all combusted tobacco products as part of a comprehensive nicotine policy.
We addressed the potential benefits, potential harms and common concerns related to reducing nicotine content of combusted tobacco.
We proposed an approach that could decouple the link between nicotine and the deadly by-products of combusted tobacco and help New Zealand achieve its goal of becoming smokefree by 2025.
Acknowledgments
ECD was supported by the University of Pittsburgh while writing this manuscript as a Visiting Professor at the University of Auckland. DH was supported by the Forster Family Chair in Cancer Prevention. ECD and DH receive research funding from the US National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products to assess the potential impact of reducing the nicotine content of cigarettes in the USA.
References
Footnotes
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Disclaimer All authors have previously undertaken clinical trials that involved the use of reduced nicotine content cigarettes. Some of the cigarettes used in these trials were purchased from companies (Vector Group, 22nd Century). The companies concerned had no role in development of the study design, data collection, data analysis, data interpretation or writing of the trial publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US Institutes of Health or the Food and Drug Administration or the New Zealand Ministry of Health.
Contributors ECD conceived the paper, wrote the initial draft, incorporated feedback from the coauthors and took responsibility for finalising the accepted manuscript. NW, DH and CB helped shape the ideas, provided substantive feedback on earlier drafts and approved of the final version.
Funding Contributions from all authors were supported by their respective institutions.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.