Nicotine

Use, Abuse, and Addiction

Tobacco smoking typically begins in adolescence, which significantly increases the likelihood of smoking in adulthood. Adolescents report being able to obtain tobacco easily. Most adolescents (95%) are aware of the health risks associated with smoking, but they report that this is of little concern. The prevalence of adolescent smoking increases with age: 12 (2%), 13 (5%), 14 (9%), 15 (14%), 16 (22%), 17 (28%). Of adolescent smokers, 75% attempt to quit, but only 30% are able to abstain for more than one month.

Figure 7.7 Effects of five consecutive cigarettes on plasma nicotine concentration in two human subjects. Thirty minutes elapsed between the end of one cigarette and the start of the next. The periods of smoking each cigarette are shown as solid bars (Subject 1) and open bars (Subject 2) beneath the X-axis. The curves coincide at the end of smoking the fifth cigarette. Blood samples were taken before smoking, 0.5, 10, and 30 min after the last puff of each cigarette, and 60 and 120 min after the fifth cigarette. These data show that individuals vary in their absorption of the absolute amount of nicotine but show similar peak and trough patterns after each cigarette, increasing blood nicotine levels overall during the course of smoking five cigarettes each. [Taken with permission from Isaac PF, Rand MJ. Cigarette smoking and plasma levels of nicotine. Nature, 1972, (236), 308–310.].

Parental smoking, older sibling and peer smoking habits, the self-medication of emotional states, and the self-medication of withdrawal have all been linked to the rapid escalation in nicotine addiction in adolescents.

Prospective studies have found that up to 50% of adolescents and young adults who had initiated smoking showed an escalation in daily smoking within 4–5 years. Various psychosocial factors, such as peer smoking and parenting style, have been suggested to contribute to the escalated smoking behavior. Studies also suggest that the symptoms of nicotine dependence, most commonly craving for tobacco and withdrawal symptoms, can develop at very early stages of initial smoking, and this early appearance of symptoms of nicotine dependence was found to predict future escalation to daily chronic smoking. In contrast, individuals who engage in non-daily smoking without escalation (“chippers”) had very few or no symptoms of dependence, and their smoking experience is primarily associated with positive rather than negative reinforcement. Thus, early tobacco use associated with withdrawal symptoms can promote the escalation of smoking behavior, which in turn accelerates the appearance of additional symptoms of dependence. The importance of negative emotional states associated with the withdrawal from tobacco use in the escalation of smoking is also suggested by the calming effects of nicotine when given after even a short period of abstinence, a primary reason given by both adults and adolescents for smoking (see Behavioral Mechanism of Action). Thus, escalation may be more common among individuals with difficulties regulating negative affect, who are prone to develop withdrawal symptoms, and who have high expectancy of the calming effects of smoking, supporting a key role for negative reinforcement in tobacco addiction (for further reading, see Tucker et al., 2003; Heinz et al., 2010).

Figure 7.8 Venous blood nicotine (A) and carboxyhemoglobin (B) concentrations in human subjects throughout the day while smoking their usual brand. The subjects smoked at least one pack per day (mean, 28 cigarettes; range, 20–40 cigarettes). These data show that individuals maintain a steady level of nicotine intake over the course of the waking day. Notice the high levels of carboxyhemoglobin that accompany such smoking. [Taken with permission from Benowitz NL, Jacob P 3rd. Nicotine and carbon monoxide intake from high- and low-yield cigarettes. Clinical Pharmacology and Therapeutics, 1984, (36), 265–270.]

TABLE 7.2

Cigarette Consumption, Type of Cigarette Smoked (Average), and Blood Nicotine and Carboxyhemoglobin Concentrations (Averages) in Men and Women

 

Men (n = 124)

Women (n = 206)

% smoking filtered cigarettes

61.3%

70.9%

% smoking unfiltered cigarettes

13.7%

1.9%

% smoking low-nicotine cigarettes (< 1.0 mg)

25.0%

27.2%

Cigarette consumption per day

36.2 cigarettes

32.6 cigarettes

Cigarette consumption on day of test

20.7 cigarettes

18.2 cigarettes

Tar yield per cigarette

17.3 mg

15.8 mg

Nicotine yield per cigarette

1.3 mg

1.2 mg

Nicotine level in blood

33 ng/ml

32 ng/ml

Carboxyhemoglobin level in blood

7.8%

8.6%

Taken with permission from Russell MA, Jarvis M, Iyer R, Feyerabend C. Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. British Medical Journal, 1980, (280), 972–976.

As smoking progresses, tolerance develops to the autonomic side effects of smoking. Several trajectories of cigarette use and dependence then follow (Figure 7.10). Once regular smoking is established, dependence rapidly follows, and regular smokers find quitting particularly difficult.

As with some other drugs, the trajectories of cigarette use have revealed a category of nondependent smokers called chippers. Chippers are defined as those who smoke fewer than five cigarettes per day. Some people remain chippers, and some become converted chippers (those who were heavy smokers previously but currently smoke fewer than five cigarettes per day; for further reading, see Shiffman et al., 1994). One study of the smoking behavior of chippers compared their smoking history and dependence with regular smokers. Chippers did not meet the criteria for Substance Dependence (addiction) on nicotine (Table 7.3). When they first started smoking, regular smokers went through a phase of approximately 2 years when they engaged in light smoking (< 5 cigarettes per day). Once they reached 15 cigarettes per day for at least 2 years (a frequency more or less defining Substance Dependence or Addiction), regular smokers never returned to chipping. In contrast, chippers smoked ≤ 5 cigarettes per day for 16 years. However, some converted chippers (29%) had previously smoked daily at a rate of ≥ 15 cigarettes per day for at least two consecutive years. The converted chippers who were previously regular smokers began their habit like regular smokers but remained chippers for 6 years. They showed a lack of dependence and decreased craving profiles, similar to non-converted chippers.

Figure 7.9 Nicotine metabolism in humans. (A) Oxidative metabolism of nicotine. (B) Quantitative disposition of nicotine in smokers. [Taken with permission from Jacob P 3rd, Benowitz NL, Shulgin AT. Recent studies of nicotine metabolism in humans. Pharmacology Biochemistry and Behavior, 1988, (30), 249–253.]

A nicotine abstinence syndrome after chronic nicotine exposure has been characterized in humans and rats, with both somatic and affective components. In humans, acute nicotine withdrawal is characterized by somatic symptoms, such as bradycardia, gastrointestinal discomfort, and increased appetite that leads to weight gain. Withdrawal is also associated with affective symptoms, including depressed mood, dysphoria, irritability, anxiety, frustration, increased reactivity to environmental stimuli, and difficulty concentrating. Anxiety, difficulty concentrating, hunger, irritability, restlessness, weight gain, and decreased heart rate are all validated signs of nicotine withdrawal in self-quitters. These symptoms begin 6–12 h after cessation, peak in 1–3 days, and then return to normal within 7–30 days (for further reading, see Hughes, 1992; Figure 7.11).

Figure 7.10 Different patterns of smoking that evolve over time as measured by (A) the number of cigarettes smoked and (B) the self-rating of addiction in subjects. Chippers were arbitrarily defined as individuals who smoked 1–5 cigarettes per day and reported no dependence. Chippers reported casual abstinence without any withdrawal symptoms or any evidence of tolerance. Converted chippers were individuals who met the criteria for chipping but had experienced extended periods of heavy smoking. These data show multiple patterns of cigarette intake and emphasize the point that not all cigarette smoking meets the criteria for dependence. [Provided with permission by Dr. Saul Shiffman, Department of Psychology, University of Pittsburgh.]

Enduring symptoms of nicotine withdrawal (protracted abstinence) in humans include a continued powerful craving that can last up to 6 months. Rates of depression did not increase with spontaneous nicotine withdrawal, but subjects who did experience an increase in depression were more likely to relapse. The somatic symptoms of withdrawal from chronic drug intake are unpleasant and annoying, but avoidance of the affective components of drug withdrawal may play a more important role in the maintenance of the tobacco habit. Although many smokers who attempt to quit are successful early on, relapse rates are high in the long-term, with only 10–20% of individuals remaining abstinent after 1 year.

Nicotine replacement therapy, including nicotine gum, nicotine patches, and sublingual nicotine tablets, reduce the occurrence of withdrawal symptoms in abstinent smokers. The efficacy of nicotine replacement therapy in smoking cessation trials is related to the ability to prevent the onset and reduce the duration of nicotine withdrawal, increasing the percentage of individuals who succeed in quitting smoking permanently. Nonetheless, only 20–30% of smokers who use nicotine replacement therapy remain abstinent after 1 year.

The strong relationship between withdrawal and negative affect, including anxiety, frustration, anger, and depressed mood, has led to another therapeutic approach to smoking cessation: antidepressant treatment. Some estimates indicate that up to 60% of smokers have a history of clinical depression, and the incidence of clinically diagnosed Major Depressive Disorder among smokers was twice as high as non-smokers. Smokers with a history of clinical depression were also significantly less likely to succeed in quitting than smokers without depressive histories (14% vs. 28%). Unknown is whether individuals who suffer depressive symptoms are more likely to become smokers or whether depressive symptoms are induced or exacerbated by long-term smoking. Tricyclic antidepressants like imipramine have shown some promise in aiding smoking cessation, but selective serotonin reuptake inhibitors like fluoxetine did not affect smoking behavior in heavy smokers. Bupropion (Wellbutrin, Zyban), an atypical antidepressant that facilitates norepinephrine and dopamine neurotransmission but not serotonin neurotransmission, was proven effective in double-blind, placebo-controlled trials. Twice the number of subjects who received 300 mg bupropion per day for 2 months remained abstinent compared with subjects treated with placebo.

TABLE 7.3

Fagerstrom Tolerance Questionnaire Items

Questionnaire from Fagerstrom KO. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addictive Behaviors, 1978, (3), 235–241.

a Canonical correlation = 0.81, Wilks’ λ = 0.35, F6,130 = 40.4, p < 0.0000001.

b Effect size is expressed as percentage of variance accounted.

c Adjustment made for differences in smoking frequency; lag to first cigarette compared to average inter-cigarette interval. Positive values indicate smoking later than expected; negative values indicate smoking sooner than expected.

d This item is not part of the original Fagerstrom Tolerance Questionnaire but relates to similar content. Analyzed with nonparametric statistics because of highly skewed distribution.

* p < 0.01,

** p < 0.001,

*** p < 0.00005,

**** p < 0.0000001.

[Taken with permission from Shiffman S, Paty JA, Kassel JD, Gnys M, Zettler-Segal M. Smoking behavior and smoking history of tobacco chippers. Experimental and Clinical Psychopharmacology, 1994, (2), 126–142.]

Figure 7.11 Self-reported symptoms before and after the cessation of tobacco use. The zero value on the X-axis indicates pre-cessation. These data show a comprehensive assessment of the different symptoms of cigarette smoking during withdrawal in humans. Notice that many of the symptoms are of a motivational nature, such as anxiety, irritability, difficulty concentrating, and depression. [Taken with permission from Hughes JR. Tobacco withdrawal in self-quitters. Journal of Consulting and Clinical Psychology, 1992, (60), 689–697.]

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