Nicotine

History of Use

Tobacco use and cigarette smoking are the most popular and persistent forms of drug taking in the modern age (Figure 7.2). The names ascribed to the plant itself have varied greatly from culture to culture, including apooke in Virginia, yetl by the Aztecs, oyngona by the Huron, sayri by the Peruvians, kohiha in the Caribbean, and cogiaba or cohiba by the Spanish. The use of Nicotiana tabacum by indigenous people in North and South America can be traced back 8,000 years, both archeologically and ethnopharmacologically, and it has been used for both medicinal and ceremonial purposes (Figure 7.3). Many historians contend that European explorers, such as Columbus in 1492, were the first to record the practice of smoking the dried leaves of the tobacco plant, probably in the form of cigars (Boxes 7.2, 7.3). European travelers to Mexico noted the medical uses of tobacco by the natives:

“In this country, tabaco cures pain caused by cold; taken in smoke it is beneficial against colds, asthma and coughs; Indians and Negroes use it in powder in their mouths in order to fall asleep and feel no pain.”

(Stewart GG. A history of the medicinaluse of tobacco, 1492–1860. Medical History, 1967, (11), 228–268.)

BOX 7.1

SYNOPSIS OF THE NEUROPHARMACOLOGICAL TARGETS FOR NICOTINE

All tobacco products contain nicotine, which is the main psychoactive ingredient in cigarette smoke. Nicotine is considered a psychostimulant, but it can also produce analgesia and anti-anxiety-like (or anxiolytic) effects. Nicotine mimics the actions of the endogenous neurotransmitter acetylcholine and binds as an agonist at nicotinic receptors. These are widely distributed throughout the brain but have high concentrations in reward-related circuits. Nicotinic receptors are ion-gated receptors. The activation of nicotinic receptors opens calcium channels to increase neuronal excitability and promote transmitter release. There are multiple nicotinic receptor subtypes that are composed of different subunits, but most form three broad groups in the brain: α2–6, β2–4, and α7–10 subunits. The α4β2 nicotinic receptor appears to be mostly responsible for the psychostimulant effects of nicotine, in addition to a wide range of behavioral and physiological effects. The psychostimulant and rewarding effects of nicotine are largely mediated by actions on nicotinic receptors in the origin areas (ventral tegmental area) and terminal areas (nucleus accumbens) of the mesocorticolimbic dopamine system and extended amygdala (central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the shell of the nucleus accumbens). The addiction potential of nicotine largely derives from powerful within-system neuroadaptations (signal transduction mechanisms) and between-system neuroadaptations (neurocircuitry changes) in the brain motivational and stress systems.

Tobacco has been used to prevent fatigue, whiten teeth, treat abscesses, heal wounds, purge nasal passages, relieve thirst, and treat syphilis. English explorers were first made aware of the existence of the plant in Florida in 1565. The plant then proliferated to other countries, including India, Japan, and Turkey. The first American colonial commercial crop was grown for export in Jamestown, Virginia, in 1612 by John Rolfe, husband of Pocahontas (the benevolent Algonquian Native American who helped save the Jamestown colony by supplying it with food during its hard times). Cultivation extended to Maryland in 1631, and Virginia and Maryland were the main producers through the 1700s. By 1630, over 1.5 million pounds of tobacco were being exported from Jamestown every year. Tobacco is now grown in 120 countries worldwide.

As mentioned above, tobacco was introduced to Europe in the 16th century, and its use has survived significant historical attempts at prohibition. Smoking tobacco was considered to be both pleasurable and also a cure for ailments. Tobacco ingestion has fluctuated between smoking, chewing, and snuffing, but one method has often been replaced with another, such as when in the early 18th century the British imported Nicotiana tabacum from Virginia in the form of snuff for medical use. By 1726, snuff had nearly eclipsed the other forms of tobacco. In what is probably an apocryphal story, the origin of the cigarette is attributed to serendipity at the siege of Constantinople by the French in the middle of the 19th century:

Figure 7.2 Marlboro cigarette advertisement, circa 1958. Notice the smoke in the photograph – absent now from contemporary advertisements. Notice also the conspicuous lack of the now-ubiquitous Surgeon General’s warning, which did not appear on cigarette packages until 1966.

Figure 7.3 Hand-colored engraving of tobacco smoking as a Floridian Native American health remedy. (de Bry T, Le Moyne de Morgues J. Brevis narratio eorvm qvae in Florida Americae Provicia Gallis acciderunt [A brief narration of those things which befell the French in the Province of Florida in America]. Francoforti ad Moenvm, Typis I. Wecheli, sumtibus vero T. de Bry, venales reperiutur in fficina S. Feirabedii, 1591.)

TABLE 7.1

Major Toxic Agents in Cigarette Smoke (Unaged)

nt: not tested.

1 85 mm cigarettes without filter tips bought on the open market 1973–1976.

2 NOx > 95% NO; remainder, NO2.

3 Not toxic in smoke of blended US cigarettes because pH < 6.5; therefore, ammonia and pyridines are present only in protonated form.

[Adapted from Wynder EL, Hoffmann D. Tobacco and health: a societal challenge. New England Journal of Medicine, 1979, (300), 894–903.]

BOX 7.2

CIGARS

Cigars can be defined as any roll of tobacco wrapped in leaf tobacco. Cigars are a tightly rolled bundle of dried and fermented tobacco that is formulated so that its smoke may be drawn into the mouth and absorbed by the mucosal lining there. Cigar smoke is more alkaline than cigarette smoke and therefore is absorbed more readily by the mucous membranes in the mouth, making it easier for the smoker to absorb nicotine without having to inhale. Some individuals inhale cigar smoke, but this is rare. Cigars allegedly date back to the time of the Mayans, and the word is derived from the Mayan “sikar” (to smoke rolled tobacco leaves). Cigars preceded cigarettes in the history of tobacco use (for further reading, see de Assis Viegas, 2008).

BOX 7.3

Elihu Root thinks that a cigar after breakfast is the smoke of the day, and there are many smokers who will agree with him. He is reported as saying: “My breakfast is a very simple meal, and consists of a cup of coffee or chocolate and a roll. When I have finished it, I light my cigar. I find that it assists me in my work. It does not aid me in the creation of ideas so much, nor in reading or actual writing; but when I want to prepare my plans for the day, when I want to arrange and put in shape the work I have before me, I find that smoking is a valuable assistant. I never smoke a large cigar in the morning, and usually do not prolong the smoke beyond the time it takes me to arrange my day’s programme. Altogether I should say that I smoke five cigars a day. I have smoked steadily for the past thirty years, and during the first ten years I smoked a pipe. It has been my experience that smoking relieved me at any time when I felt overworked. Consequently, if I find at any time of day that my brain is getting tired, and that my ideas are getting muddled, I stop and light a cigar. I don’t think that smoking has a sedative effect upon me, but it composes my thoughts and soothes me to some extent.”

From: Bain J Jr., Tobacco Leaves, H.M. Caldwell Company, Boston, 1903.

“It is told in Alsace, France, the following story that if apocryphal, has nevertheless the merit to be plausible. At the siege of Constantinople (today’s Istanbul) in 1854, an Alsacian Zouave soldier had his pipe pulled out of his teeth by a shell fragment. Not knowing how to smoke his remaining tobacco, he had the idea of rolling it into a tube made of paper. Therefore, it was an accident of war that gave birth to the cigarette, and we all know the comfort it would bring to all soldiers and civilians during the coming wars, whiling away the long hours of anticipation, hunger, and depression.”

(Translated from Haug H. Petite Histoire du Tabac en Alsace, Strasbourg, 1961.)

However, reference is also made to another form of smoking that also resembles the cigarette. An early 16th century expedition to Mexico noted that the natives would pack tobacco and liquid ambar (a herb) into a hollow reed that was allowed to smolder on one end, with the smoke inhaled from the other. According to some, this wrapping evolved from reeds to corn husks to paper used for manufacturing cigars in Spain. The Peninsular War fought by France against the Portuguese, British, and Spanish in the early 19th century disseminated these new, smaller cigars from Spain to France. The French renamed it the “cigarette.” The Crimean War of the mid-19th century introduced it in England, where, in 1856, Robert P. Gloag set up a factory in Walworth for mass production. Aromatic tobaccos were used in these new cigarettes because they were the only types of tobacco suitable for smoking in this form. Flue-cured aromatic tobacco and air-cured Burley tobacco were introduced in 1864 for further mildness. These flue- and air-cured tobaccos were substituted for some of the aromatic tobaccos to form the blended cigarette in America in the late 1800s. The first cigarette-making machine was introduced in 1880. From there, tobacco and cigarette production accelerated through the end of the century, attributable to the convenience of the smoking vehicle, ease of production, transportation, distribution, mass media advertising, and demand (Figure 7.4).

Tobacco smoking continues to be a worldwide health problem. The high addictive potential of nicotine is reflected by the vast number of people who habitually smoke and relapse (Box 7.4). The 2011 United States National Survey on Drug Useand Health from the Substance Abuse and Mental Health Services Administration estimated that 173.9 million people aged 12 and older (67.5%) had ever engaged in tobacco use, and 81.9 million people aged 12 and older (31.8%) were last-year users of tobacco. Additionally, 161.8 million people aged 12 and older (62.8%) had ever engaged in cigarette use, and 67.1 million people aged 12 and older (26.1%) were last-year users of cigarettes. Notable statistics from the survey included the following. In 2011, of those people aged 12 or older who ever used in the last year, 22.9 million (34.2%) showed cigarette dependence (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV], criteria). There is no abuse category for tobacco or cigarettes, so any statistics for substance dependence will be identical to those for tobacco use disorders. The World Health Organization has reported that more than 1.3 billion people smoke daily worldwide.

The cost to society is significant in terms of health problems that frequently lead to death, high medical costs, and human suffering. Tobacco smoking is the leading, avoidable cause of disease and premature death in the United States. In 2008, the US Centers for Disease Control and Prevention reported that cigarette smoking and exposure to secondhand smoke caused an estimated 443,000 deaths and 5.1 million years of potential life lost during 2000–2004. A 2008 CDC report found that smoking was implicated in 41% of the deaths from cancer, 32.7% of the deaths from cardiovascular disease, and 26.3% of the deaths from respiratory disease. On average, smoking shortens life span by 13 years in males and 15 years in females. Tobacco addiction accounts for 3.7% of DALYs worldwide, and this percentage increases to 10.7% in high-income countries.

Maternal smoking during pregnancy is associated with lower birth weight, with heavy smokers reducing the birth weight of their offspring by 226 grams on average. Much more seriously, maternal smoking is now the single most important preventable risk factor for Sudden Infant Death Syndrome. Sudden Infant Death Syndrome results from developmental delays in the neural control of cardiopulmonary function (Box 7.5). The children of smokers are also more likely to have respiratory diseases, such as asthma, and maternal smoking is significantly associated with increased risks of addiction to both tobacco and other drugs of abuse during adolescence, which is likely mediated by alterations in drug reward circuitry. Some of these effects may be directly related to nicotine itself. Neurobiological bases exist for the toxic effects of nicotine on the brain, and they follow the transient increases in nicotinic acetylcholine receptor (nAChR) expression within a given brain structure that coincides with the most crucial phases of development. For example, nAChRs critically regulate catecholamine and autonomic development in the prenatal period, hippocampal and cerebellar development during the early postnatal period, and limbic and postnatal catecholamine development during the adolescent period, providing the substrates by which nicotine can alter cardiopulmonary function, immune function, and motivational function, respectively (for further reading, see Dwyer et al., 2009).

Figure 7.4 Trends in per capita consumption of various tobacco products in the United States (in pounds) from 1880 to 2000 among persons aged 18 years or older. After the year 2000, the latest data indicate the following per capita consumption for all tobacco products (the latest comparable data end in 2006): 4.3 in 2001, 4.2 in 2002, 4.0 in 2003, 3.9 in 2004, 3.7 in 2005, and 3.7 in 2006. [Data from the US Department of Agriculture Tobacco Situation and Outlook Report series. Figure from Koob GF, Le Moal M. Neurobiology of Addiction. London: Academic Press, 2006.]

BOX 7.4

Edwin Booth was a fierce smoker. His favorite was a pipe, not a cigar. He smoked in his dressing-room, between acts, in his own room, constantly, and I am not sure that he did not smoke in bed. He loved tobacco as another man might love food and drink. His system was full of nicotine, for he overdid it, and he would be alive today if he had been a moderate smoker, as would General Grant... ...The fiercest smoker whom I have ever known was the late Francis Saltus, the marvelous linguist, musician, composer, writer, and traveler. He would smoke (surely) fifty cigarettes a day. You talk about fellows smoking in bed and between courses at a dinner? Well, Frank Saltus would smoke between mouthfuls. I have seen him smoke fifty cigarettes in a day, while turning out two or three hundred dialogs (“squibs,” he called them) for the papers and magazines. He was a wonder, look at him how you will, and some day the world will know it.

From: Bain J Jr., Tobacco Leaves, H.M. Caldwell Company, Boston, 1903.

BOX 7.5

SUDDEN INFANT DEATH SYNDROME

Definition: Death from the sudden cessation of breathing (apnea) of a seemingly healthy infant, almost always during sleep, sometimes traceable to chronic oxygen deficiency.

An even more surprising finding in the neurotoxicity of tobacco is that a grandmother’s tobacco use is associated with an increased risk of early childhood asthma, even if the mother did not smoke while pregnant. In an animal model of prenatal nicotine exposure, maternal nicotine exposure exerted adverse effects on lung development, not only for the immediate offspring but also for the next generation. Such a phenomenon is termed an epigenetic effect (Box 7.6), further emphasizing the important deleterious effects of smoking during pregnancy (for further reading, see Leslie, 2013).

BOX 7.6

EPIGENETICS

Definition: The study of the way in which the expression of heritable traits is modified by environmental influences or other mechanisms without a change in the DNA sequence.

A study sponsored by the World Health Organization and the World Bank estimated that in the United States, smoking-related healthcare expenses accounted for 6% of all annual healthcare costs. Overall, nicotine addiction costs the United States $155 billion annually. A graphic summary of the health toll of tobacco addiction is that:

“Smokers lose at least one decade of life expectancy, as compared with those who have never smoked. Cessation before the age of 40 years reduces the risk of death associated with continued smoking by about 90%.”

(Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, McAfee T, Peto R. 21st-century hazards of smoking and benefits of cessation in the United States. New England Journal of Medicine, 2013, (368), 341–350.)

Other forms of nicotine delivery include waterpipe smoking, smokeless tobacco, and electronic cigarettes. A non-cigarette mode of tobacco ingestion, waterpipe smoking, has its roots in ancient India and has been used for over 400 years. Waterpipe smoking has been steadily spreading among young people around the world in the past 10 years. Studies at universities in the United States reported in 2010 that the proportion of people who had ever used water pipes ranged up to 30%, and current waterpipe use ranges up to 20%. A “waterpipe” generally refers to the device or the tobacco use method in which smoke passes through water before it is inhaled. Many different names are associated with waterpipe smoking, including argileh, goza, shisha, and hubble-bubble, but the name hookah has gained generic status. A typical waterpipe consists of four main parts (Figure 7.5): the bowl, where the tobacco is burned; the base, filled with water; the stem, which connects the bowl to the base; and the hose and the mouthpiece, through which smoke is inhaled. A different type of tobacco preparation is used in waterpipes, which is both flavored and sweetened, and is referred to as Massel. Various flavors, including apple, blackberry, cappuccino, and mint, provide smokers with distinct cues of a pleasant smoking experience because of the sweet smell and smooth taste of the sweetened tobacco. The attraction of this type of method of tobacco use among young people may be related to its pleasant smooth smoke, social ambience, and the perception of reduced harm. One form of waterpipe involves placing burned charcoal pieces on top of a perforated aluminum foil that separates it from a flavored tobacco mixture. When the smoker draws air through the hose’s mouthpiece, charcoal-heated air becomes smoke as it passes the tobacco mixture and cools as it bubbles through the water of the waterpipe before inhalation by the smoker. This alleged “filtering” is the basis for the misconception of “reduced” harm and “reduced” addiction potential. Waterpipes are smoked at “hookah bars,” establishments that are becoming widespread in large cities across the United States. Recent research suggests that waterpipe smoking can be addictive and produce a substance use disorder-like syndrome. For example, although data are limited, waterpipe smoking is linked to the same cardiovascular and pulmonary diseases as cigarette smoking, with the addition of communicable diseases from sharing waterpipes and mouth pieces (for further reading, see Maziak, 2011; Noonan and Kulbok, 2010; Eissenberg and Shihadeh, 2009).

Figure 7.5 Trends in per capita consumption of various tobacco products in the United States (in pounds) from 1880 to 2000 among persons aged 18 years or older. After the year 2000, the latest data indicate the following per capita consumption for all tobacco products (the latest comparable data end in 2006): 4.3 in 2001, 4.2 in 2002, 4.0 in 2003, 3.9 in 2004, 3.7 in 2005, and 3.7 in 2006. [Data from the US Department of Agriculture Tobacco Situation and Outlook Report series. Figure from Koob GF, Le Moal M. Neurobiology of Addiction. London: Academic Press, 2006.]

Smokeless tobacco can be defined as either chewing tobacco or snuff and is also a significant health concern. Adverse health consequences of smokeless tobacco use include oral (gum and buccal mucosa) cancer in smokeless tobacco users who chew quid or tobacco. According to the US National Survey on Drug Use and Health, in 2011, 8.2 million people aged 12 and older (3.2%) used smokeless tobacco, and 1.9 million people aged 18–25 had used a smokeless tobacco product in the past month.

The rapid growth of electronic cigarette use worldwide points to another potential health problem associated with nicotine. Electronic cigarettes deliver nicotine through the battery-powered vaporization of a nicotine/propylene-glycol solution; thus, electronic cigarettes (e-cigarettes) are hypothesized to be less harmful than regular cigarettes because they deliver nicotine without the various toxic constituents of tobacco smoke. Currently, 3.4% of the total population, including 11.4% of current smokers, 2.0% of former smokers, and 0.8% of never-smokers, reported using e-cigarettes (for further reading, see Pearson et al., 2012). Most smokers claim to use e-cigarettes for smoking cessation/reduction, and their use appears to enhance the motivation to quit. To date, studies show that blood nicotine levels generated by e-cigarettes are low to moderate, but e-cigarette use reduced craving and partially alleviated withdrawal symptoms. The compulsive-like use of e-cigarettes remains to be investigated.

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