Nicotine and Tobacco

Definitions

Cigarette smoking is the most frequent (>90%) method of tobacco use, although other forms, including pipe tobacco, cigars, and smokeless tobacco, are common. Nicotine, which is the active ingredient in tobacco, acts as a reinforcer for the use of all forms of tobacco. In recent years, however, vaping of nicotine through electronic nicotine delivery systems (ENDS; e-cigarettes without tobacco) now constitutes more than 30% of nicotine use in the United States.

Epidemiology

Cigarette smoking is the leading cause of morbidity and mortality in the Western world. In the United States as of 2022, about 14% of the general population (approximately 65 million adults) are tobacco users, compared with about 47% in 1965. As the health risks of environmental tobacco smoke became increasingly clear, smoking has been banned in many public settings. However, the rate of decline has slowed in recent years, likely because the remaining smokers are refractory. Approximately 500,000 people in the United States die each year as a result of smoking-attributable medical illnesses such as lung cancer ( Chapter 177 ), head and neck cancer ( Chapter 176 ), bladder cancer ( Chapter 182 ), chronic obstructive pulmonary disease ( Chapter 76 ), cardiovascular disease ( Chapter 40 ), and stroke ( Chapter 376 ). The economic and health care costs of tobacco use exceed $400 billion annually. Smokeless tobacco (e.g., chewing tobacco) use has also increased and has contributed to higher rates of oral conditions, including precancerous oral lesions ( Chapter 393 ) and cancers of the mouth and nasopharynx ( Chapter 176 ).

Worldwide, an estimated 1.1 billion people use tobacco on a regular basis. Tobacco smoking is increasing rapidly throughout the developing world, and cigarette smoking causes about 7.7 million deaths worldwide each year. In particular, the onset of smoking now occurs at a younger ages, the rates of smoking in women are increasing, and more smokers are of a lower socioeconomic status. Reducing smoking prevalence by 50% could prevent about 150 million premature deaths in the second quarter of this century. For most smokers, quitting is the single most important behavior change to improve overall health. Since the relationship between smoking and the risk of tobacco-related illness is present even at very modest daily smoking levels, sustained reductions (>25 to 75%) in daily smoking consumption are of little to no benefit, thereby substantiating the merits of quitting versus reducing smoking.

Pathobiology

Nicotine is the primary reinforcer in tobacco, with contributions from over 400 components to the sensory (non-nicotine) aspects of cigarette smoking. Nicotine’s primary site of action is the α4β2 nicotinic acetylcholine receptor (nAChR) at which acetylcholine is the endogenous neurotransmitter. nAChRs in the central nervous system (CNS) are pentameric ion channel complexes that are comprised of two α and three β subunits; the eight α subunits are designated α2 to α9, and the three β subunits are designated β2 to β4. These multiple receptors produce considerable diversity in subunit combinations, which may explain the region-specific and functional selectivity of nicotine’s effects in the CNS. Activation of nAChRs leads to Na ⁺ /Ca ²⁺ ion channel fluxes and neuronal membrane depolarization. nAChRs are located presynaptically on several neurotransmitter-secreting types of CNS neurons, including mesolimbic dopaminergic neurons that project from the ventral tegmental area to the nucleus accumbens, thereby leading to the secretion of dopamine, which contributes to the reinforcing effects of smoking. Long-term smoking causes hypomethylation of the aryl hydrocarbon receptor repressor gene, but this epigenetic change is reversible after smoking cessation.

At low nicotine concentrations, α4β2 nAChR stimulation of afferent gamma-aminobutyric acid (GABA)-ergic projections onto mesoaccumbal dopaminergic neurons predominates, thereby leading to reduced firing of mesolimbic neurons and reduced release of dopamine. At higher nicotine concentrations, α4β2 nAChRs desensitize, and predominant activation of α7 nAChRs on glutamatergic projections leads to increased mesolimbic neuron firing and release of dopamine. Within milliseconds of nicotine binding, nAChRs desensitize. After overnight abstinence, nAChRs resensitize, likely explaining why most smokers report that the first cigarette in the morning is the most satisfying. Interestingly, positron emission tomography (PET) neuroimaging studies show that smoking two to three puffs from a cigarette saturates nAChRs in the brain reward system, thereby suggesting that although binding to central nAChRs is an important first step in the effects of nicotine, it is not a complete explanation for persistent smoking behaviors.

In addition, the non-nicotine effects of smoking appear to reinforce the habit. Taken together, molecular and trans-synaptic nicotine effects and the biobehavioral effect of non-nicotine components appear to contribute to the high rates of smoking initiation, maintenance, and relapse in both tobacco smokers and users of e-cigarettes.

Clinical Manifestations

cigarette smoking. Although a subset of cigarette smokers do not smoke every day (e.g., “chippers”), most cigarette smokers are daily users and have physiologic dependence on nicotine. Nicotine has both stimulating and anxiolytic effects depending on basal level of arousal (i.e., it is stimulating during boredom but reduces anxiety during stress). Smokers typically describe a “rush” and feelings of alertness, relaxation, and “satisfaction” when smoking.

Airway stimulation is an important aspect of smoking behavior, and the positive effects of cigarette smoking (e.g., taste, satisfaction) appear to be mediated by non-nicotine components of tobacco, such as tar, menthol, and other additives, which enhance the experience by reducing the harshness of nicotine and other components of tobacco.

In addition to the positive attributes of nicotine and other additives, smoking is stimulated by craving and withdrawal owing to the addictive properties of nicotine. Secondary effects that may contribute to both smoking maintenance and relapse include mood modulation (e.g., reduction of negative affect), stress reduction, and weight control. In addition, conditioned cues (e.g., people, places, things, emotions associated with nicotine and tobacco use) can elicit the urge to smoke even after prolonged periods of abstinence.

Nicotine may benefit smokers who hope to lose weight, and its pharmacologic actions can enhance mood and cognition while reducing stress. These secondary effects may present additional targets for pharmacologic intervention in subgroups of smokers (e.g., anxious, depressed, or weight-concerned smokers). Although nicotine is the primary reinforcer associated with tobacco smoking behaviors, the non-nicotine components (e.g., tars) that give tobacco its taste and satisfaction are polycyclic aromatic hydrocarbons that are responsible for its high risks of cancer (e.g., lung, colon, brain) and of cardiovascular and pulmonary diseases.

secondhand smoke. Secondhand smoke, which is generated while the cigarette is smoldering as well as when smoke is exhaled by the smoker, represents 75% or more of the total combustion product of a cigarette. Some toxins (e.g., ammonia, formaldehyde, and nitrosamines) actually have higher concentrations in secondhand smoke than in inhaled smoke. Secondhand smoke is a class A carcinogen that also increases the risks of myocardial infarction, cough, aggravation of asthma and chronic obstructive pulmonary disease, eye irritation, nasal congestion, and headache.

smokeless tobacco. Chewing tobacco is actively chewed and generates saliva that is spit out, whereas oral snuff is placed (as a “pinch”) between the lip and gum or under the tongue. Smokeless tobacco products are usually flavored, often with licorice, and contain sodium bicarbonate to maintain an alkaline pH that facilitates buccal absorption of nicotine. As a result, the absorption of nicotine is of similar magnitude to cigarette smoking. Sodium, glycyrrhizinic acid (from the licorice), and carcinogenic chemicals (e.g., nitrosamines) are absorbed systemically.

Because of its nicotine content, smokeless tobacco is as addictive as cigarette smoking. Users also have increased rates of cancer at the site where the tobacco is usually placed orally (inside the lip, under the cheek or tongue) or for users of nasal snuff, nasal cancers ( Chapter 176 ). Users of smokeless tobacco also are more likely to develop oral leukoplakia, gingivitis, gingival recession, and staining of the teeth. As with smoking tobacco, smokeless tobacco increases cardiovascular risks and can acutely aggravate hypertension or angina pectoris because of the sympathomimetic effects of nicotine. Furthermore, smokeless tobacco contains glycyrrhizinic acid (a potent mineralocorticoid) that can precipitate hypokalemia, hypertension, and excessive sodium absorption, thereby exacerbating sodium retention and hypertension.

Diagnosis

Tobacco use disorder is established clinically by historical documentation of two of the following 11 criteria:

• 1.

  Tobacco often taken in larger amounts or over a longer period than was intended;

• 2.

  Persistent desire or unsuccessful efforts to cut down or control tobacco use;

• 3.

  A great deal of time spent in activities necessary to obtain or use tobacco;

• 4.

  Presence of craving, or a strong desire or urge to use tobacco;

• 5.

  Recurrent tobacco use resulting in failure to fulfill major obligations at work, school, or home;

• 6.

  Continued tobacco use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of tobacco;

• 7.

  Important social, occupational, or recreational activities given up or reduced due to tobacco use;

• 8.

  Recurrent tobacco use in situations in which it is physically hazardous (e.g., smoking in bed);

• 9.

  Continued tobacco use despite persistent or recurrent physical or psychological problems that are caused or exacerbated by tobacco use;

• 10.

  Tolerance, as defined by either a need for markedly increased amounts of tobacco to achieved desired effects, or markedly diminished effects with continued use of the same amount of tobacco;

• 11.

  Withdrawal, manifested by the presence of the characteristic tobacco abstinence syndrome (i.e., four of the following: irritability, anxiety, difficulty concentrating, increased appetite, restlessness, dysphoric mood, insomnia), or tobacco (or nicotine) is taken to relieve or avoid tobacco withdrawal symptoms.

The current severity of tobacco use disorder is coded as mild (two to three symptoms), moderate (four to five symptoms), or severe (six or more symptoms). For abstinent smokers, remission is classified as early (between 3 and 12 months of abstinence) or sustained (>12 months of abstinence).

Most physiologically dependent tobacco smokers state that they smoke their first cigarette of the day within the first 5 minutes of awakening. Retrospective timeline follow-back questions regarding prior use and prospective smoking diaries have been used successfully to monitor smoking consumption.

Treatment