Nicotine is the primary addictive component in cigarettes and other tobacco products. It establishes and maintains addiction, thereby sustaining use, through a range of complex actions on brain neurochemistry.
The addictiveness of any nicotine-containing the product depends on several factors beyond merely the presence of nicotine. These factors primarily include the rate at which nicotine is absorbed and delivered to the brain, and the dose of nicotine delivered. Other factors, such as the speed at which the drug is metabolised and how soon withdrawal symptoms occur, play a role. This is particularly relevant to nicotine, given its short half-life (about 2 h), but this is a feature of the drug more than the product delivering the drug. A nicotine-containing product will, therefore, be more or less addictive depending on the dose and rate at which the nicotine is delivered. Essentially, a product that delivers a high dose rapidly will have greater liability for addiction than one that delivers a low dose slowly. In this section, we describe the importance of these factors.
The dose is an important factor in the development of nicotine dependence. Animal models clearly demonstrate an inverted-U relationship between nicotine dose and self-administration, although there is interindividual variability in the shape of this curve, some of which is under genetic influence1. Therefore, increasing the dose is associated with increased self-administration up to a point, after which higher doses become increasingly aversive and ultimately toxic. One advantage of the short half-life of nicotine is, however, that it enables consumers to self-titrate their achieved dose. The dose (ie plasma concentration) of nicotine achieved via the use of different nicotine-containing products varies considerably.
Nicotine is metabolised principally in the liver, with a half-life for elimination of approximately 2 h (although this varies considerably between individuals). As a result of this short half-life, plasma nicotine concentrations drop rapidly after nicotine administration, leading to withdrawal symptoms, prompting further nicotine administration in regular users, eg in a typically heavy, dependent smoker, nicotine levels increase rapidly after smoking a cigarette (by about 5–30 ng/mL), then drop before increasing again after smoking the next cigarette. Over the course of a day, plasma nicotine concentrations rise gradually to a steady state of between about 10 and 50 ng/mL.2. Critically, overnight abstinence leads to the almost-complete elimination of nicotine from the body, leading to marked withdrawal on waking, and the need to consume nicotine in order to reverse these symptoms.
The addictive potency of cigarettes (and indeed other tobacco products) is influenced by not only their nicotine content but also other aspects of product design, including substances added to the cigarette to enhance nicotine delivery and absorption. Monoamine oxidase (MAO) inhibitors in tobacco smoke increase the levels of amines in the brain, such as dopamine and serotonin, and may subsequently potentiate the reinforcing effects of nicotine3. Indeed, animal studies have demonstrated that MAO inhibitors facilitate nicotine self-administration and enhance its motivational properties4 5. These findings may also contribute to the strong reinforcing properties of nicotine from cigarettes. Sugars and polysaccharides are commonly added to tobacco products6 to increase the formation of aldehydes, including formaldehyde and acetaldehyde, in tobacco smoke. Acetaldehyde itself has addictive potential7 as demonstrated through self-administration experiments in animals8, but it also enhances the addictive potential of nicotine. The interaction between these compounds also generates a rewarding effect that exceeds the additive effects of either component in rodent studies.
Menthol and other flavourings (including cloves and liquorice) increase the palatability of cigarette smoke and, in the case of menthol and cloves, facilitate deeper inhalation and therefore a higher nicotine dose (owing to their cooling/local anaesthetic effects). These are widely added at levels below those used in what are conventionally considered to be ‘flavoured’ cigarettes. Flavours may also become conditioned reinforcers in themselves, as a consequence of their repeated pairing with nicotine9. In addition, menthol inhibits metabolism of nicotine to cotinine, purportedly through inhibition of CYP2A6 enzyme activity10, thus increasing the effect of nicotine. Cocoa and chocolate, which contain theobromine, are also common additives in tobacco. Theobromine is a bronchodilator, and thus has been proposed to enhance nicotine absorption in the lungs. However, the theobromine content of cigarettes was deemed too low to exert bronchodilatation in a recent review11. Levulinic acid is an additive with a sweet caramel taste, but it also alters the pH and so reduces the ‘harshness’ of inhaled smoke12. This, similarly to menthol, facilitates a higher nicotine dose.
Alkaline additives such as ammonia compounds are among the most common additives used in cigarette manufacture13. These substances are added to cigarettes (and other tobacco products) to manipulate the pH. Increasing the pH increases the proportion of non-ionised, or freebase, nicotine, which is more physiologically active than the ionised form, crossing biological membranes more readily. Tobacco industry scientists have extensively investigated the potential of pH manipulation to optimise nicotine delivery. Curing methods used in the production of tobacco can also influence the pH of tobacco smoke. In particular, air-cured tobacco, as used in cigars, generates nicotine at a relatively high pH, facilitating absorption from oral and upper airway mucosa. Cigarette tobacco is largely flue-cured, resulting in nicotine at a lower pH and lower upper airway absorption, hence requiring inhalation into the much larger surface area of the lung alveoli to achieve significant absorption.
Royal College of Physicians (RCP) (2016). Nicotine without smoke: tobacco harm reduction. A report by the Tobacco Advisory Group of the Royal College of Physicians. https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction