NICOTINE

OFFICIAL NAMES: Nicotine, tobacco

STREET NAMES: Cigarettes, pipes, cigars, bidis (beedies), kreteks (clove cigarettes), spit tobacco (spit), chewing tobacco (chew), snuff

DRUG CLASSIFICATIONS: Not scheduled, stimulant

OVERVIEW

Nicotine dependence is almost invariably caused by addiction to tobacco, because tobacco is the overwhelming source of nicotine. Nicotine present within tobacco products causes physical and mental effects rapidly leading to addiction, and the user continues using tobacco despite adverse health consequences and usually a desire to stop. The widespread use of tobacco, despite its known dangers, probably reflects its low cost and easy availability, its high level of social acceptance until recent years, and its seemingly mild immediate side effects.

Nicotine use often begins in adolescence in response to commercial and social pressures and continues because of the positively reinforcing effects of nicotine, which can include both relaxation and increased alertness. In later stages of use, smoking may be used mainly to relieve withdrawal symptoms such as irritability and discomfort.

Addictive characteristics of nicotine

Nicotine meets the criteria for causing chemical dependence with the following characteristics:

• Users can exhibit tolerance, which is when additional amounts of nicotine are required to produce an effect.
• A great deal of time may be spent using nicotine (such as leaving work for cigarette breaks), and it is usually taken in larger amounts or over longer periods of time than was intended.
• Users may have a persistent desire for nicotine (craving) and unsuccessful attempts to cut down or control its use.
• Nicotine causes withdrawal symptoms, and its ingestion may continue despite knowledge of the harm it causes.
• Daily tobacco use becomes compulsive, repetitive, and imperative.
• The user avoids withdrawal symptoms and experiences the rewards by repeated dosing, that is, by ingesting more nicotine from tobacco products.
• There is a high rate of relapse once use ceases.

Nicotine dependence resembles that of alcohol, heroin, and cocaine but appears to be more harmless to smokers for two reasons. First, there are usually several years or decades before signs of disease are detected. Second, smoking does not produce a disabling state of intoxication seen with the other drugs. On the contrary, nicotine may improve attention or decrease fatigue and therefore improve performance.

Increased risk of developing dependence

Risk of dependence and disease increases with the number of cigarettes smoked and duration of smoking. There is a marked increase in dependence when use exceeds five cigarettes daily. The earlier individuals start to smoke, the more severe their addiction will be.

People with anxiety and depression are at greater risk of dependence as nicotine is used as a "self-medication" to enhance mood. Youths with adjustment problems, who are risk takers, or have extraverted (outgoing) personalities are at increased risk for smoking. Children whose parents are regular smokers are at high risk.

Genetic factors influence the risk of nicotine addiction, as with other addictive substances. Inheriting certain genes can either contribute to or help protect individuals from nicotine addiction. In some cases, the genetic vulnerability to nicotine addiction may be linked to a similar vulnerability to alcohol dependence. Genetic differences in dopamine receptors and rate of nicotine breakdown have been shown to effect the likelihood of nicotine dependence.

Introduction into society

Ingestion of nicotine is an ancient and widespread practice. Native North, Central, and South Americans have smoked, chewed, sniffed, and drank tobacco preparations for thousands of years. It was used in religious and ceremonial rituals, as a medication, and to suppress hunger. The word tobacco is derived from tobaga pipes used by Central American natives.

Christopher Columbus brought the practice back to Europe where it was first used for its medicinal properties. French diplomat Jean Nicot, for whom nicotine is

named, helped popularize its use to treat a wide array of illnesses: upset stomachs, ulcers, headaches, toothaches, constipation, and asthma. It was also used as a poultice and antiseptic for cuts, burns, and sores.

Nonmedical pipe smoking, chewing, and snuff were initially limited to sailors who had adopted the Native American habit but spread rapidly from Europe to Africa and Asia in the early 16th century. At the same time, there was strong condemnation of tobacco use on both health and social grounds. Popes and kings banned its use, perhaps slowing its spread as its popularity increased.

The commercial tobacco industry in North America began in the Jamestown colony in 1612 and grew to be one of the most important national crops over the next 200 years. By the early 1960s pipe smoking and snuff gave way to cigars and cigarettes with the development of a cigarette-rolling machine and the safety match. Cigarette consumption increased during both World Wars, and mass marketing caused a dramatic jump in cigarette use during the next several decades.

The height of the smoking epidemic in the United States was in 1965 when 52% of adult men and 32% of adult women smoked. Attitudes of Americans had slowly begun to change by the 1950s when long-term studies clearly linked tobacco and disease. Progress was made nationwide to decrease smoking rates using public health announcements on television, education in schools, increases of federal excise taxes, and warning labels on cigarette packages. In 1971 cigarette advertising was banned from television and radio, and during that same year the nonsmokers' rights movement began. Social acceptability of smoking began to fall, reinforced by the 1986 Surgeon General's report focusing on the hazards of environmental tobacco smoke to nonsmokers. By the end of the century, less than 25% of adults smoked, but the rate of decline slowed dramatically in the 1980s and 1990s for both men and women.

General impact today

Tobacco use, particularly smoking, is the number one cause of preventable death in the United States, causing 20% of all deaths. Smoking is a major risk factor for heart disease, stroke, lung and other forms of cancer, and chronic lung diseases—all leading causes of death. It is a major risk factor for a variety of other medical conditions as well.

There are at least 434,000 deaths attributable to smoking per year in the United States, almost 1,200 per day, one every 73 seconds. This death rate is higher than the combined total of deaths due to AIDS, alcohol, cocaine, heroin, homicide, suicide, motor vehicle crashes, and fires. Approximately half of all continuing smokers die from diseases caused by smoking. Of these, approximately half die between the ages 35 and 69, losing an average of 20 to 25 years of life expectancy. Continued smoking throughout life doubles age-specific mortality rates, nearly tripling them in late middle age.

Estimates of disease due to smoking do not include the contribution of smoking to overall poor health status. Poor general health may decrease survival for many diseases, including those not caused by smoking, and may limit the treatment options available to the patient. For example, a smoker with emphysema may not be a safe candidate for a surgery needed to treat another medical problem.

Reducing tobacco use

Despite overwhelming evidence for the adverse health effects of tobacco use, smoking habits have been difficult to change. Nicotine addiction, along with heavy promotion by the tobacco industry, maintains high levels of use. The Centers for Disease Control and Prevention (CDC) estimates that the average 14-year-old has been exposed to more than $20 billion in advertising since age six, creating a "friendly familiarity" with tobacco products. In1999, total advertising and promotional spending by the tobacco companies rose to $8.24 billion, more than $22 million per day. However, education, combined with community-wide and media-based activities, can postpone or prevent smoking onset in 20% to 40% of adolescents.

Studies show that the best ways to reduce tobacco use combine:

• restrictions or outright bans on tobacco advertising and promotion
• raising excise taxes on tobacco products
• enforcement of smoke-free environments in public areas and worksites
• banning of tobacco sales in vending machines
• warning labels on tobacco products and advertisements
• continuous education, especially for minors, on health effects of smoking
• a minimum age of 18 for sellers of tobacco products
• citation of storeowners who sell tobacco to minors
• licensing of tobacco-selling establishments plus compliance checks

The FDA was unsuccessful in its attempt from 1995 to 2000 to have nicotine named as a drug and cigarettes named as a drug delivery device and thus subject to FDA control. Such control would have had the potential to severely restrict promotion and access to tobacco products.

CHEMICAL/ORGANIC COMPOSITION

Nicotine (C₁₀ H₁₄ N₂, beta-pyridyl-alpha-N methylpyrrolidine) is a very poisonous, water-and lipid-soluble, liquid alkaloid with a burning taste. It is colorless, but turns brown and takes on the odor of tobacco upon exposure to air. First isolated in 1828, it is used as an insecticide in agriculture, and as a killer of parasites in veterinary medicine.

Tobacco plant leaves of two species, Nicotiana tobacum and the milder flavored Nicotiana rusticum, generally contain 2–8% nicotine. The average cigarette contains between 8 and 10 mg. Some nicotine is lost from the tobacco leaf during the curing (slow drying in sun, hot air, or smoke), storing, and manufacturing processes. The NCI points out that each can of chewing tobacco holds a lethal dose of nicotine. Also, each tin of snuff delivers as much nicotine as 30–40 cigarettes, with4.5–6.5 mg nicotine per pinch. Holding a pinch of snuff in the mouth for 20–30 minutes yields nicotine levels two to three times the amount of nicotine delivered by a regular-size cigarette.

Burned tobacco contains some 4,800 distinct chemicals in either gas or particle phases. Many of the compounds in both phases are highly reactive, poisonous, and toxic. Harmful products include oxidants and poisons produced during burning, as well as radioactivity, heavy metals, and pesticides that may have accumulated within the tobacco leaf. Sixty-nine of these substances are known to cause cancer in humans and animals, and many others are known to be strong irritants.

The gaseous phase contains the harmful gases carbon monoxide (CO) and nitrogen oxide, along with carbon dioxide, ammonia, hydrogen cyanide, benzene,

toluene, formaldehyde, acetone, acetaldehyde, methanol, and vinyl chloride. CO is a byproduct of the incomplete burning of tobacco and is thought to be a major culprit in causing cardiovascular (heart) disease.

The compounds of the particle phase are collectively called tar, or total particulate matter (TPM). Tar is the oily residue left behind when moisture evaporates from burned tobacco. It contains thousands of compounds, including cancer-causing aromatic amines, nitrosamines, and polycyclic aromatic hydrocarbons that are present in both smoking and smokeless tobacco. Other harmful constituents include radioactive lead and polonium as well as arsenic, among others.

Additives

The manufacturers of tobacco products add fillers, flavor enhancers, preservatives, and other additives to make the product more desirable to consumers, especially low-tar brands. Each company's list of additives was a closely guarded trade secret until 1984, when the lists were submitted to the government. The public was barred from seeing the lists until 1994. The initial list contained 700 potential additives, of which 13 are not allowed in food. One additive, ammonia, may be included to boost the absorption of nicotine and enhance the addictive "kick." Sweeteners and chocolate may help make cigarettes more attractive to children and first-time users.

Menthol is commonly added to certain brands as it numbs the throat to the irritating effects of smoke. Menthol opens up the lung passages and allows more smoke to be inhaled deeper into the lungs. It makes the lungs more permeable to tars and carcinogens (cancer-causing agents), causing greater disease. These cigarettes also boost nicotine and CO levels. Menthol cigarettes accounted for 26% of the market in 1999.

Low tar and nicotine cigarettes and compensatory smoking

In the 1950s tobacco companies introduced filters on cigarettes to try to remove some of the toxins in smoke. By 1999, 98% of United States smokers used filter-tipped cigarettes. The companies then made other changes to the cigarette to further reduce the amount of tar and nicotine delivered to the smoker. Such changes included altering the composition of the tobacco and adding ventilation holes in the filter to dilute smoke with air. The average tar yield has fallen from 37 mg to 12 mg since 1968. The average nicotine yield fell from 2.7 mg to 0.85 mg.

In theory, filters and other changes to decrease the amount of tar and nicotine in cigarettes should decrease the health hazards of smoking. In fact, the mortality risk among current smokers has risen in the last 40 years even though tar and nicotine levels have fallen. Many smokers of low-yield brands compensate by taking deeper, longer, or more frequent puffs from their cigarettes to get the nicotine their body desires. They may hold the smoke longer in their lungs before exhaling or smoke the cigarette further down. This is referred to as "compensatory smoking." They may also increase the amount of tar and nicotine taken into the lungs by unintentionally blocking tiny ventilation holes in the filter with their fingers or lips. The smoker may end up inhaling as much or more tar and nicotine as in regular brands. Additionally, low tar products may also have higher levels of CO, and a variety of other toxins.

Kreteks and bidis

Increasing numbers of teens are turning to alternative cigarettes called bidis, tiny flavored cigarettes from India, and kreteks or clove cigarettes from Indonesia. Bidis (or beedies) are small, unfiltered cigarettes, handrolled in leaves. Flavorings such as chocolate, strawberry, and vanilla are added to the American versions of bidis to make them more appealing to minors. Bidis contain more than three times the amount of nicotine and five times the amount of tar than regular cigarette smoke. They are also puffed more frequently than regular cigarettes to prevent them from going out.

Kreteks contain tobacco and 40% shredded clove buds. They have a pleasant, sweet aroma of cloves, but have such high levels of tar, nicotine, and CO, that smoking one is equivalent to smoking 20 light American cigarettes. Eugenol, the local anesthetic in cloves, permits the inhalation of the harsh smoke.

INGESTION METHODS

Nicotine is ingested by smoking shredded tobacco in cigarettes, cigars, and pipes, or through smokeless tobacco. Smokeless tobacco comes in two major forms: snuff and chewing tobacco. Snuff is cured, ground tobacco manufactured in three varieties: dry, moist, and fine cut. Chewing tobacco is coarser than snuff and is also produced in three forms: loose-leaf, plug, and twist.

Today, moist snuff is usually taken orally, similar to chewing tobacco. Usually a pinch of snuff or a plug of chewing tobacco is placed between the gum and cheek, or the leaves or plug are chewed. Saliva mixes with the tobacco, and nicotine is absorbed through the lining of the mouth. This moist tobacco is referred to as a "chaw" or "quid" of chewing tobacco or a "dip" or "pinch" of snuff. It may be kept in the mouth for hours, and the user expectorates (spits out) the saliva that mixes with the tobacco. Dry snuff, which is less commonly used, is usually inhaled through the nose.

Absorption and metabolism

Nicotine is easily absorbed through all body surfaces including the lungs, oral and nasal passages, skin, and gastrointestinal tract. Absorption is influenced by the pH (acidity) of the smoke or chew. Cigarette smoke is acidic, and therefore the nicotine is best absorbed through the alveoli (tiny air sacs) of the lungs during deep inhalation. Cigar and pipe smokers typically do not inhale the alkaline smoke, and nicotine absorption, like that of smokeless tobacco, occurs through the lining of the mouth. Inhalation provides the quickest route of nicotine delivery to the brain and is therefore the most addictive. Absorption through the mouth is slower and through the skin slower yet.

Nicotine in chewing tobacco is absorbed in the first 10 minutes, with peak levels occurring within 30 minutes. The nicotine from a puff of cigarette reaches the brain within 10 seconds. With approximately 10 puffs per cigarette, a pack per day delivers 200 doses (hits) of this potent drug to the brain. The repeated, frequent peaks in nicotine levels in the brain and blood contribute to its addictiveness.

The smoke is 1% to 2% nicotine and approximately 1–3 mg of the drug reaches the smoker's bloodstream per cigarette. Half of the nicotine is eliminated from the blood in 30 to 120 minutes. This short half-life is the result of a portion of nicotine in the blood being metabolized (broken down or changed into other substances) in the liver, lungs, and other organs. Primarily, it is oxidized into cotinine, a less active substance. The kidney then rapidly removes nicotine and cotinine from the body.

The short half-life of nicotine contributes to its abuse potential. The initial effects drop off after a few minutes, causing the user to continue self-administering nicotine throughout the day to maintain pleasurable effects and prevent withdrawal symptoms. Studies clearly show that animals will self-administer nicotine intermittently to avoid both very low and very high levels of nicotine.

THERAPEUTIC USE

Nicotine is most often used in replacement therapy for tobacco addiction, but also has some potential uses to treat other conditions. It has been helpful in stopping bleeding in ulcerative colitis. Nicotine gum is being tested in conjunction with Tourette syndrome where it has been seen to lessen the severity and frequency of tics. Nicotine may reduce tremors in Parkinson's patients because it increases dopamine levels, which are reduced in these patients. It also improves attention in Alzheimer's patients. Nicotine is being studied for its effect on dystonias (movement disorders), chronic pain syndrome, sleep apnea, ulcers, attention deficit disorder, obesity, and chronic inflammatory skin disorders as well.

USAGE TRENDS

Scope and severity

Cigarette smoking is the most common substance use disorder in the United States. A billion cigarettes were produced in the entire United States in 1885. Today over one billion are smoked daily. Nationally, there were 48 million adult (18 years and older) smokers in 2001. The average smoker smokes 20 cigarettes per day.

Low-income adults smoke more than high-income adults. People with less education smoke more than those with college degrees. Habitual users of alcohol, cocaine, and heroin are more likely to be smokers too. More than 80% of alcoholics are smokers, and alcoholic drinkers are at least twice as likely to be smokers than are nondrinkers. The highest prevalence rates are seen with psychiatric patients: up to 88% of schizophrenics smoke, and approximately 50% of patients with anxiety, personality disorders, and depression smoke. Forty percent of adults with attention deficit hyperactivity disorder (ADHD) smoke.

However, the 2001 smoking rate of 25% is markedly decreased from the height of the smoking epidemic in 1965, when 42% of adults over 18 years old smoked. More than half of the smokers in the United States since the mid-1960s have quit. However, following years of steady decline, rates showed only modest declines in the 1990s.

The consumption of cigars has been increasing since 1993 with growing popularity among younger, affluent people. In 1998, 5% of adults had smoked a cigar product in the last month. Pipe smoking is in decline, with only 2% of men in partaking in 1991, and very uncommon usage among women. Pipe smoking is mainly found in men over the age of 45, who are also likely to be users of other tobacco products, especially cigarettes. National data from 1999 shows 6% of adult men and 1% of women use chewing tobacco or snuff. But the popularity of smokeless tobacco is increasing, especially among younger white males.

Gender trends

Historically, smoking became prevalent among men before women, but the gap between male and female smoking rates narrowed in the mid-1980s and has remained constant. The American 2001 smoking rate of 28% men and 22% women decreased from the 1965 peak, when 52% of men and 32% of women smoked. In developing countries, 48% of males smoke. Rates among women are substantially lower (7%) but increasing.

The prevalence of smoking during pregnancy has declined steadily in recent years, although 13–22% of pregnant women continue to smoke. Only about one third of women who stop during pregnancy are still abstinent one year after the delivery.

Studies indicate that men and women differ in their smoking behavior. Women tend to smoke fewer cigarettes per day than men, are more likely to use filtered or low-tar and -nicotine cigarettes, and inhale less deeply. Women are less likely to use smokeless tobacco, cigars, or pipes than men are. Correspondingly, lung cancer rates are lower in women than men. However, in 2001, the United States Surgeon General noted a 600% increase since 1950 in women's death rate from lung cancer, primarily caused by previous decades of cigarette smoking.

Age trends

Most tobacco users begin the habit in their teens. Initiation and addiction to smoking occurs in 90% of tobacco users by their eighteenth birthday. Every day in the United States, more than 6,000 young people try a cigarette, and almost 3,000 become regular smokers. First-time cigarette use is most likely to occur between ages 11 and 15, in sixth through tenth grade. A long-term national study found that 70% of high-school seniors who smoked as few as one to five cigarettes a day were still smoking five years later, and most were smoking more cigarettes per day. Tobacco is often the first drug used by young people who go on to use alcohol, marijuana, and other drugs.

In 1999, 44% of male students and 37% of female students reported using some form of tobacco (cigarettes, cigars, or smokeless tobacco) in the past month. Thirty-five percent of high-school students were current smokers, including 39% of white students, 33% of Hispanic students, and 20% of African American students. The 2000 rate of high school use of bidis was 5% and5.8% for kreteks.

Overall, the percentage of American high-school students who smoked increased through the mid-1990s after declining in the 1970s and 1980s. The CDC found that the sharpest rise in daily smoking rates began in 1988, the year the Joe Camel advertising campaign began. A study released in 2001 shows that high school smoking levels peaked in 1997 and have since made steady progress downward. The decline is attributed to several factors, including decreased advertising targeted at youth, increased anti-smoking advertising, and increased prices of cigarettes.

Adolescent boys are shifting from smoking to smokeless tobacco partly due to the mistaken belief that it is a safe substitute for smoking. Nationwide in 2000, 4% of middle school boys and 12% of high school boys used chewing tobacco or snuff. White male students were more likely than Hispanic or African American male students to use smokeless tobacco. The median age for first use of smokeless tobacco is 12, two years younger than the median age for first use of cigarettes.

An increasing number of boys and girls are experimenting with cigars, unaware that the risks are similar to cigarette smoking. In 1999, an alarming 25% of high school males, and 10% of high school females were using cigars. White students are more likely than African American students to smoke cigar products.

Ethnic trends

Multiple factors determine patterns of tobacco use among racial and ethnic minority groups in the United States: socioeconomic status, cultural characteristics, degree of assimilation into American culture, stress, biological elements, targeted advertising, price of tobacco products, and the varying capacity of communities to mount effective tobacco control initiatives.

Between 1983 and 1995, cigarette smoking declined for whites (34% to 26%), African Americans (37% to 27%), Hispanics (30% to 19%), and Asian and Pacific Islanders (24% to 15%). The prevalence of tobacco use among Native American and Alaskan Natives stayed at 41% between 1983 and 1995.

The American Heart Association smoking statistics for the year 2000 are as follows:

• Native American men: 38%; women: 31%
• African American men: 32%; women: 22%
• Caucasian American men: 27%; women: 23%
• Hispanic American men: 26%; women: 14%
• Asian and Pacific Islander American men: 22%; women: 12%

It is important to note that although African Americans do not have the highest smoking rates of racial groups in the United States, they appear to bear the greatest adverse health effects, particularly lung cancer in males. Some studies propose that the use of mentholated cigarettes by 80% of African Americans might be a cause.

Occupational and workplace trends

Professional, technical workers, and clergy have the lowest smoking rates whereas the military, law enforcement, and blue-collar workers have the highest rates. More adults are taking up the smokeless tobacco habit if they are no longer allowed to smoke on the job. Professional baseball players have an alarmingly high rate of 35% to 40% chewing tobacco use, and approximately half of those have pre-cancerous lesions of the mouth.

Larger employers with over 100 workers are more likely to adopt restrictive smoking policies, compared to smaller companies. Hospitality, service, and blue-collar workplaces in manufacturing and processing industries are less likely to be smoke-free environments.

Global trends

Tobacco use is one of the major causes of preventable death in the world. The estimated 1.2 billion smokers in the world consume an average of 14 cigarettes per day. In the year 2000, 4.2 million deaths were due to tobacco use, and the figure is expected to rise to 10 million deaths annually by the year 2030. Seven million of those deaths are expected to occur in developing countries. While smoking rates are slowly declining in developed nations, they are steadily growing in developing nations at a rate of 3.4% per year. Smoking will eventually kill about 500 million people alive in the world today. One billion people will die from tobacco in this century.

MENTAL EFFECTS

Nicotine has several effects that are due to its action on the brain. Beginning smokers may experience dizziness or lightheadedness and sometimes vertigo. At higher doses, nausea and vomiting may occur. These effects can also be elicited in chronic smokers with forced, rapid smoking. Most smokers learn to avoid such unpleasant effects by adjusting their inhalation patterns.

Studies have indicated that there are two major pleasurable effects of nicotine ingestion that reinforce the habit: stimulation (vigilance, wakefulness) and relaxation. Tobacco users may feel that smoking helps them concentrate and feel clear headed, and studies do show that nicotine causes an improvement in attention, recall, information processing, reaction time, and problem solving. Smokers may also feel that smoking helps them relax in stressful situations or that it lifts their mood. They may feel calm and experience less anger, tension, depression, and stress. Both stimulation and relaxation may be experienced at the same time, resulting in a state of relaxed wakefulness.

Nicotine is known to bind to acetylcholine receptors (the receiving areas on cells) that are located throughout the central nervous system as well as the peripheral nervous system. Acetylcholine is a neuro-transmitter: it transmits nerve impulses from one nerve fiber to another. The pleasurable effects of nicotine are a

direct result of nicotine binding to these acetylcholine receptors, which then triggers the release of other neurotransmitters and hormones. Epinephrine, dopamine, norepinephrine, acetylcholine, serotonin, vasopressin, and beta-endorphin are all released. Epinephrine (adrenaline) release results in a "rush" or "kick" as it stimulates the body, increasing heart rate, blood pressure, breathing rate, and blood sugar. The wide variety of chemical messengers in the following list adapted from Neal L. Benowitz (1999) may explain the diverse, and sometimes seemingly opposite effects of nicotine (stimulation and relaxation) reported by smokers:

• Dopamine causes pleasure and appetite suppression.
• Norepinephrine causes mental stimulation and appetite suppression.
• Acetylcholine causes mental stimulation and cognitive (thinking) enhancement.
• Vasopressin causes memory improvement.
• Serotonin causes mood enhancement and appetite suppression.
• Beta-endorphin causes a reduction of anxiety and tension.

Furthermore, nicotine may have different effects at different doses. Rapidly delivered, increasing doses are likely to cause a stimulating reaction, whereas slower, chronic intake has a more calming, sedating effect.

Nicotine is thought to cause addiction primarily through its action to increase the levels of dopamine, which activates the brain circuitry that regulates feelings of pleasure and motivation, the so-called reward system. Increased dopamine in this system produces pleasurable sensations, as seen in other drugs of abuse such as cocaine and heroin.

Substances in smoke other than nicotine may also affect the brain. An unknown substance in smoke causes a decrease in the level of monoamine oxidase (MAO), an important enzyme responsible for breaking down dopamine. The decrease in MAO results in higher dopamine levels, which contributes to the desire to keep smoking.

The desire to smoke can also be brought on by reinforcing factors called "external stimuli" such as the sight, taste, and smell of tobacco smoke, as well as the social setting and rituals associated with smoking. These previously neutral stimuli in the environment, or certain events, can become associated with tobacco use and thus become triggers for a desire to smoke.

PHYSIOLOGICAL EFFECTS

Immediate effects

As with the mental effects of nicotine, the physiological effects are brought about by its actions on the nervous system, both peripheral and central. Nicotine changes the transmission of nerve impulses by binding to acetylcholine receptors, and induces the release of several chemical messengers, which in turn affect several body systems.

In the cardiovascular system, there is a 10 to 20 beat per minute increase in heart rate, a 5–10 mm increase in blood pressure, and an increase in the strength of heart contractions. Nicotine increases the incidence of cardiac arrhythmia (irregular heartbeat) in susceptible people. It causes constriction of blood vessels in the skin, and causes platelets to adhere together leading to an increased possibility of blood clots.

Nicotine is irritating to the digestive tract. Salivation increases, and the strength of stomach contractions decreases. Nausea and vomiting may occur. Appetite is suppressed, particularly in females for sweet food. Metabolism is increased and brown fat is stimulated, which along with appetite suppression can lead to weight loss.

Nicotine causes local irritation in the respiratory system, as well as decreased motion of the cilia, the tiny hairs that sweep debris and mucus upward, out of the respiratory tract. A recurrent "smoker's cough" results as the body tries to rid itself of accumulated mucus. Breathing is accelerated by nicotine.

In the endocrine (gland secretion) system, besides increased release of epinephrine and norepinephrine, there is increased release of the growth hormone, cortisol, and the antidiuretic hormone. The increased levels of circulating catecholamines (epinephrine, norepinephrine, and dopamine) play a role in causing cardiovascular diseases by changing the balance of lipoproteins circulating in the blood. They increase the harmful low-density lipoproteins (LDL) and decrease the protective high-density lipoproteins (HDL), increasing the risk of cardiovascular disease.

Nicotine toxicity

Ingestion of 60 mg of nicotine can be fatal to an adult. This is an amount that might be ingested with exposure to some insecticide sprays. A smaller amount is toxic to children and pets who accidentally ingest tobacco products. Tobacco pickers and patients on nicotine replacement therapy who continue to smoke have also experienced nicotine toxicity. Symptoms include salivation, dizziness, vomiting, tremors, convulsions, and severely low blood pressure. Death may result in a few minutes due to respiratory failure caused by lung paralysis.

Carbon monoxide and tar

It is important to emphasize that although nicotine causes a wide variety of physical and mental effects, the majority of health problems from smoking are due to carbon monoxide and tar, much more so than nicotine. CO decreases the ability of the blood to carry oxygen. This leads to an increased production of red blood cells to compensate for the loss of oxygen carrying capacity. Along with nicotine, CO contributes to lipoprotein changes and increased blood-clotting ability, leading to cardiovascular disease. Tar, with its many known carcinogens and other irritants, is largely responsible for various forms of cancer, especially lung cancer.

Withdrawal syndrome

An attempt to stop using tobacco products, or even decrease their consumption, often results in the user experiencing unpleasant withdrawal symptoms that are due specifically to nicotine. Symptoms may start within hours after cessation of use, peak usually at the second to fourth day and may last for weeks or months.

Withdrawal symptoms include:

• restlessness
• anxiety
• impatience
• irritability or anger
• difficulty concentrating
• excessive hunger
• depression
• disorientation
• loss of energy or fatigue
• decreased heart rate and blood pressure
• dizziness
• stomach or bowel problems
• headaches
• sweating
• insomnia
• heart palpitations
• tremors
• decreased motor performance
• increased muscle tension
• craving for tobacco products

The symptoms are often worse in the evening. Weight gain is common, 4–7 lb (2–3 kg) on average.

Among tobacco users with no history of depression, 20% experience depression during withdrawal. The rate jumps to 80% for those with a past history of depression. Women are more prone to depression during withdrawal than men.

Long-term health effects

Smoking causes one third of all cancers and 87% of lung cancer. Because of tobacco use, lung cancer is the number one cancer killer of both men and women. It is also associated with cancer of the mouth, throat, voice box, esophagus, stomach, bladder, kidney, pancreas, uterus, and cervix. Smoking is also possibly linked to leukemia, and cancer of the breast, prostate, and colon. The overall rates of death from cancer are twice as high among smokers as among nonsmokers, with heavy smokers having death rates that are four times greater than nonsmokers. The role of nicotine itself in causing cancer is controversial.

The majority of smoking-related illnesses are cardiovascular and respiratory. Nearly one fifth of heart disease deaths in the United States are related to smoking. It is a major cause of atherosclerosis (narrowing and hardening of the arteries) and high blood pressure and the resulting angina, heart attacks, and strokes due to both hemorrhage and blood clots. It also increases the risk of abdominal aortic aneurysm.

Smoking leads to respiratory problems other than lung cancer. It causes chronic bronchitis, emphysema, and lower resistance to flu and pneumonia. It worsens asthma symptoms in adults and children. As these problems persist, chronic obstructive pulmonary disease (COPD, airway obstruction) develops. Eighty to 85% of deaths due to COPD are from smoking. The role of nicotine in chronic lung diseases such as COPD, emphysema, and asthma is uncertain. However it is known that nicotine can cause an enzyme to be released which is able to destroy parts of the lungs as is seen in emphysema.

Smoking is especially harmful to diabetics who are already at an increased risk of cardiovascular disease, stroke, and kidney disease. The habit also negatively affects joints and interferes with the healing of wounds. Healing of fractures is delayed because smoking impairs the formation of new bone. Smokers are more likely to develop degenerative disorders and injuries of the spine. The risk for peptic ulcers is increased. Smoking also may upset thyroid function.

Heavy smoking is a contributory factor in male impotence due to a decreased amount of blood flowing into the penis. Smoking also increases the risk of infertility in men by decreasing sperm motility and density. A nearly twofold increase in hearing loss, cataracts, and macular degeneration of the eye has been observed in smokers. Smokers have a decreased sense of taste and smell and are prone to periodontal disease, such as receding gums, as well as increased dental cavities.

Women

Women face additional adverse health effects from smoking. About 30% of cancers of the cervix are attributable to both active and passive smoking. Women who smoke have a high risk for osteoporosis and hip fractures following menopause. They are likelier to have early onset of menopause due to nicotine's anti-estrogen effect. However, the decreased estrogen levels seen in female smokers appear to decrease their risk of endome-trial cancer up to 50%. Women smokers have an increased risk of infertility, especially those women who started before age 18 or who smoke one or more packs per day. In 1987, lung cancer surpassed breast cancer as the leading cause of cancer death among women.

Pregnancy

Pregnant women who smoke create additional health concerns for their unborn child. Many substances in tobacco smoke, including nicotine, cross the placenta and are found in breast milk. Mothers who smoke heavily have almost a two-fold increase in miscarriage and birth defects and are more likely to deliver low-birth-weight babies. Smoking during pregnancy also causes ectopic pregnancy, premature births, and stillbirths. Infant mortality rates in pregnant smokers are increased 33%.

Sudden infant death syndrome (SIDS) is strongly linked to smoking in pregnant women and new mothers. Children of smoking mothers are more likely to have motor control problems, perception impairments, symptoms of hyperactivity, and conduct disorder in childhood. These children have a higher risk for cancer later in life.

Teens

The younger a person begins smoking, the greater the risk of developing serious illnesses. Smoking teens experience adverse health effects, including a general decrease in physical fitness, increased coughing and phlegm, greater susceptibility to respiratory illnesses, and early development of artery disease (a precursor to heart disease). They have a slower rate of lung growth, and by adulthood, possible reduced lung function.

Cigars and pipes

Cigars and pipes have health consequences similar to those of cigarettes, including nicotine dependence, heart disease, and cancer of the lung, mouth, throat, voice box, esophagus, prostate, bladder, and possibly the pancreas. Additionally, pipe smoking causes cancer of the lip. Inhaling cigar or pipe smoke significantly raises the risk of disease.

Smokeless tobacco

Smokeless tobacco causes cancer of the mouth, esophagus, and stomach. Users who swallow the tobacco or the saliva increase their risk of esophageal damage and stomach ulcers. Dentists report seeing users with leukoplakia (pre-cancerous lesions) in the mouth, receding gums, dental cavities, chronic mouth sores, with badly discolored teeth, and bad breath. Smokeless tobacco may also contain high levels of sodium, which may contribute to high blood pressure.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

Smoking causes the liver to produce more enzymes that break down a variety of drugs, resulting in lower than expected blood levels. It may be necessary to monitor smokers who take other drugs on a long-term basis, and adjust their doses during smoking cessation. These medications include asthma drugs such as theophylline (Slo-Bid, Theo-Dur), blood thinners such as warfarin (Coumadin), antipsychoitc drugs such as Clozapine (Clozaril), migraine drugs such as ergotamine, and some tricyclic antidepressants. Nicotine is also reported to decrease the blood-pressure-lowering effects of drugs such as nifedipine (Procardia), atenolol (Tenormin), and propanolol (Inderal).

Women who use birth control pills should not smoke as they are at increased risk for heart attacks, blood clots, stroke, liver cancer, and gallbladder disease. The risk increases with age (especially over the age of35) and smoking more than 15 cigarettes per day.

TREATMENT AND REHABILITATION

Nicotine and tobacco dependence is best treated as a chronic condition with remission and relapse. Up to 80% of tobacco users say they would like to quit. About one third of smokers try to quit each year, 90% of these without treatment, but only 2.5–5% are successful. Of those who try to quit without treatment, more than 90% fail, with most relapsing within a week. Most people experience relapses and require repeated attempts before achieving long-term abstinence. However, effective treatments do exist, and eventually 50% of smokers succeed in permanently quitting.

Attempts to quit tobacco use should focus on small steps toward future abstinence. Cigarette smokers who try to change to other forms of tobacco, such as pipes or cigars, are still at significant risk of disease. All forms of tobacco use entail serious adverse health effects and continued nicotine dependence. Turning to low-yield or smaller cigarettes, or smoking only part of a cigarette rarely works due to compensatory smoking.

A comprehensive treatment approach ideally has two parts: handling symptoms of withdrawal, and changing habits and social settings associated with tobacco use. The various forms of treatment include drug therapy, behavioral therapies, and general support. Drug treatment of nicotine addiction, combined with behavioral support, will enable 20–25% of users to remain abstinent one year following treatment. Several effective over-the-counter (OTC) and prescription drugs are available. Some medications involve significant cost, especially if a prescription is required, but are less expensive than the cost of continuing tobacco use.

Nicotine replacement therapy

The greatest danger of nicotine dependency is related mostly to the tobacco rather than nicotine itself. Nicotine replacement therapy (NRT) is far safer than tobacco use. Although the ultimate goal is to stop ingestion of nicotine, temporary nicotine replacement therapy is useful in dealing with withdrawal symptoms. Each type of NRT helps to approximately double the achievement of abstinence when used properly but should be combined with behavioral therapy and support. These forms of nicotine have little abuse potential since they do not produce the pleasurable effects of tobacco products. Seriously ill people, pregnant women, and breastfeeding women should consult a physician when considering NRT. All tobacco use should be avoided during NRT to prevent nicotine toxicity.

Nicotine gum (Nicorette) was introduced in 1984 and is currently sold without prescription in two and four mg doses. The user chews the gum briefly and then "parks" it between the cheek and gum so that nicotine can be absorbed through the lining of the mouth. Normally nicotine gum is used two to three months. Optimal usage may involve 10–20 pieces per day. Heavier smokers should use the four mg dose.

Nicotine skin patches (NicoDerm CQ, Nicotrol, Habitrol, ProStep) were introduced in 1991 and 1992, and are sold OTC or by prescription. Nicotine in the patch is absorbed through the skin (transdermally) in different strengths, for 16 or 24 hours a day. The release of nicotine through the skin is continuous and thus provides steady concentrations of nicotine in the blood. The 16-hour patch is removed at night for those experiencing sleeping difficulty. Patches are easy to use and only applied once per day; but dosing is not flexible, onset of symptom relief is slow, and mild irritation can occur at the patch site. Recommended use is six weeks with either constant or decreasing strengths.

Nicotine nasal spray (Nicotrol NS) requires a prescription. Introduced in 1996, the nasal spray delivers nicotine through the lining of the nose when it is squirted into each nostril once or twice an hour. This method provides the fastest delivery of nicotine of the currently available products and reduces cravings within minutes. However, this form has a greater potential for inappropriate use. Nose and eye irritation is common, but usually stops within one week.

Nicotine inhaler (Nicotrol Inhaler) requires a prescription. Introduced in 1998 and designed to look like a cigarette, the inhaler is a plastic cylinder holding a cartridge containing nicotine. Nicotine is absorbed through the lining of the mouth when the user puffs on the inhaler. Each cartridge lasts for 80 long puffs and is designed for 20 minutes of use. A minimum of six cartridges per day is needed for three to six weeks, when usage begins to taper off. This product mimics the hand to mouth ritual of smoking and delivers nicotine faster than the patch, but frequent use during the day is required, and mouth or throat irritation may occur.

Non-nicotine medication

In 1996 the FDA approved the antidepressant buproprion (Zyban) for the treatment of nicotine dependence. This sustained-release pill blocks nicotine's pleasurable effects and helps to maintain abstinence whether the user has depression or not. The length of suggested use is for seven to 12 weeks, including one to two weeks before quitting tobacco. Buproprion doubles the quit rate and has been demonstrated to be safe when used jointly with NRT.

Clonidine (Catapres), a high blood pressure medication, can be prescribed orally or as a patch for nicotine addiction and doubles the quit rate. It appears to reduce craving for tobacco but does not consistently reduce other withdrawal symptoms. The antidepressant nortriptylene (Pamelor) triples the quit rate. However, both have greater side effects than those previously listed, and are considered second-line therapies.

Other medications that have been studied for nicotine addiction but were found to yield poor or variable results include naltrexone, naloxone, lobeline, mecamylamine, and buspirone. Hypnosis and herbal remedies have been reported to be of potential use but are not scientifically proven. A review of nine studies of acupuncture therapy for smoking cessation shows it to increase the quit rate a modest 1.5 times.

Education, counseling, and behavioral strategies

Knowledge of the seriousness of adverse health effects due to tobacco use is helpful in motivating a user to quit, as well as maintaining abstinence. Physicians who advise their patients to quit smoking can produce cessation rates of 5–10%. Thus, education plays a critical role in tobacco cessation for all ages. A variety of self-help materials (books, tapes, pamphlets, newsletters, software, and Internet sites) are available to inform and aid in quitting tobacco use.

Having a strong motivation to quit tobacco use is usually not sufficient motivation to quit. Other key factors to successful cessation include avoiding smokers and smoking environments and receiving support from family and friends. Even then, most users will require some further assistance beyond self-help materials to successfully quit.

Individual and group counseling by trained therapists is beneficial to those trying to quit tobacco. Over the past decade, this approach has spread from primarily clinic-based, formal smoking-cessation programs to numerous community and public health settings. Two of the most widely available offerings are the American Cancer Society Fresh Start program and the American Lung Association Freedom From Smoking program. These group programs consist of multiple sessions using behavior modification techniques. The goals of behavioral methods are to reduce the reinforcing value of smoking, discover high-risk relapse situations, create an aversion to smoking, develop self-monitoring of smoking behavior, learn coping strategies, and establish alternative rewards. Coping skills are essential for both short-and long-term prevention of relapse. A form of aversive conditioning, called rapid smoking, leads to good quit rates but dangerously high blood nicotine levels.

Groups with problems quitting

Women and African Americans have greater difficulty quitting tobacco use. NRT does not seem to reduce craving as effectively for women as it does for men. Women seem to be less sensitive to nicotine than men, but more sensitive to external stimuli—the sight, smell, and touch involved in smoking. Women have greater concerns about weight gain, restrictions on medication during pregnancy, and influences of the menstrual cycle on mood. Cessation programs should be tailored for women to rely less on NRT and more on behavioral support.

African Americans are more likely than whites to try to quit smoking, but less likely to succeed. This group apparently metabolizes nicotine differently from other racial and ethnic groups. Nicotine uptake is almost 30% higher in African American smokers than white smokers, and elimination from the body is slower than with other groups. Higher nicotine blood levels over a longer period result in stronger nicotine dependence and more difficulty quitting.

Health benefits of smoking cessation

Immediate benefits of smoking cessation include a return to normal blood pressure and pulse rate. Levels of CO and oxygen in the blood return to normal within eight hours. Within 24 hours the chance of heart attack decreases, and within 48 hours nerve endings start to re-grow and the ability to taste and smell increases. In two to three weeks lung capacity has increased, and there is improved breathing and fewer respiratory ailments. In the next one to nine months, there is a decreased incidence of coughing, sinus infection, shortness of breath, and an increase in overall energy. Cilia re-grow in the airways, which increases the body's ability to handle mucus, clean the lungs, and reduce the chance of infection. There is reduced constriction of blood vessels in already diseased heart patients.

Heavy smokers and long-time smokers are at the greatest risk of disease, so they also have the most to gain from quitting. The decreased risk of disease varies with each disease state depending on how long the smoker has abstained. The risk of death from cardiovascular disease among former smokers approximates that of nonsmokers once the smoker has been tobacco-free for 15 years. The risk of death from lung cancer or COPD is essentially unchanged for the first five years following cessation but then declines steadily from five to 20 years. However, even beyond 20 years cessation, the risk of death due to lung cancer or COPD remains elevated above that of nonsmokers. Quitting smoking substantially decreases the risk of esophageal, mouth, voice box, pancreatic, bladder, and cervical cancers. Smokers who quit before age 50 cut their risk of dying in the next 15 years in half.

Cost effectiveness of treatment

Treating nicotine and tobacco dependence can prevent a variety of costly chronic diseases, including heart disease, cancer, and chronic lung disease. It is estimated that smoking cessation efforts are more cost effective than other commonly provided preventive services such as screening for breast, colon, and cervical cancer, treatment of mildly elevated blood pressure, and treatment of high cholesterol.

PERSONAL AND SOCIAL CONSEQUENCES

The personal consequences of nicotine dependence are clearly the potentially life threatening illnesses that tobacco causes. Additional negative consequences become evident as tobacco use becomes less socially acceptable. Unlike the use of other recreational drugs or alcohol, tobacco use does not alter consciousness or cause escape from social responsibility. Therefore, until recently, smoking was regarded as a matter of personal choice. The links between second-hand smoke and disease in nonsmokers altered that view. Smokers often must face isolation and the outdoor elements to avoid exposing family, friends, and coworkers to second-hand smoke. Even then, they may face negative feedback from those around them.

Smoking causes several cosmetic changes too. Tobacco stains teeth and fingers. Smoke odor on breath, clothes, and hair may be offensive to others. Smokers are nearly five times more likely to develop more and deeper skin wrinkles, and have a higher risk for baldness and prematurely gray hair.

Environmental tobacco smoke

The smoke from smoldering tobacco together with exhaled smoke are called environmental tobacco smoke (ETS), second-hand smoke, or passive smoke. ETS is classified by the Environmental Protection Agency as a class A carcinogen (proven cancer-causing substance). The smoldering tobacco, called "sidestream smoke," contains more toxic byproducts than the inhaled/exhaled "mainstream smoke," which is burned more completely as it is drawn through the cigarette.

ETS increases the risk of heart disease and lung conditions, especially asthma and bronchitis in children. In 2000, the National Cancer Institute (NCI) estimated that 3,000 lung cancer deaths, and as many as 40,000 cardiac deaths per year among adult nonsmokers in the United States can be attributed to ETS. Passive smoke also causes increased angina symptoms, allergic attacks, eye irritation, headaches, cough, and nasal symptoms. ETS is linked with low birth weight babies, sudden infant death syndrome (SIDS), and increased pneumonia and middle ear infections in children. More than 88% of nonsmokers in the United States, aged four years and older, have detectable levels of serum cotinine, an indication of ETS exposure.

Costs

Tobacco use has the highest cost to society of any substance of abuse, with the possible exception of alcohol. The American Lung Association estimated in the year 2000 that direct medical costs of tobacco-caused illness were approximately $50 billion. However, this cost is well below the total medical costs to society because it does not include such costs as burn care from smoking-related fires, and hospital care for low birth-weight infants of mothers who smoke.

Additionally, tobacco use creates an estimated $47 billion in indirect costs such as lost productivity. Smokers of one pack of cigarettes per day have 50% greater illness, absenteeism, and rate of hospitalization than nonsmokers. In 1996 the United States Department of Health and Human Services estimated the total cost of tobacco use to businesses to be more than $5,000 per employee per year

LEGAL CONSEQUENCES

Tobacco is a legal substance when purchased and used by adults. Despite widespread efforts to prevent minors from purchasing tobacco, a high proportion continues to do so. All 50 states ban the sale of tobacco to anyone under the age of 18, but many of the laws are weak and enforcement is generally poor. Various studies demonstrated that 32% to 87% of underage youths were able to purchase cigarettes over the counter.

A growing number of states and localities are imposing penalties, usually in the form of citations, against minors who purchase tobacco products. Less frequently, when the store is cited, the penalty is usually directed against the sales clerk rather than the business owner. The result is that the business owner, who sets store policy and gains financially from the illegal sale, is free from penalty.

A working group of States' Attorneys General recommended in 1994 that enforcement focus on commercial sellers of tobacco products before targeting the youth users. Most states already require licensing of stores selling tobacco, but the group further recommended unannounced compliance checks and graduated fines and license suspension for repeated sales to minors.

RESOURCES

Books

Baer, Andrea. Quit Smoking for Good. Freedom, CA: The Crossing Press, 1998.

Brigham, Janet. Dying To Quit, Why We Smoke and How We Stop. Washington, DC: Joseph Henry Press, 1998.

Fisher, Edwin B., and Toni L. Goldfarb. 7 Steps to a Smoke-Free Life, American Lung Association. New York: John Wiley & Sons, Inc., 1998.

Whelan, Elizabeth M. Cigarettes: What the Warning Label Doesn't Tell You: The First Comprehensive Guide to the Health Consequences of Smoking. Amherst, NY: Prometheus Books, 1997.

Periodicals

DeLucia, Anthony J. "Tobacco Abuse and Its Treatment." American Association of Occupational Health Nurse Journal 49, no.5 (May 2001): 243-259.

Lewis, C. "Every Breath You Take. Preventing and Treating Emphysema." FDA Consumer 33, no.2 (March-April): 9-13.

Other

Freedom From Smoking Online. American Lung Association online smoking cessation clinic. <www.lungusa.org/ffs/>.

TobaccoPedia: The Online Tobacco Encyclopedia.<http://tobaccopedia.org>.

U.S. Public Health Service. Centers for Disease Control and Prevention. Tobacco Information and Prevention Source (TIPS).<www.cdc.gov/tobacco/index.htm>. U.S. Public Health Service. Reports of the Surgeon General.<www.surgeongeneral.gov/library/reports.htm>

World Health Organization. Tobacco Free Initiative.<http://tobacco.who.int/>.

Organizations

American Lung Association, 1740 Broadway, 14th Floor, New York, NY, USA, 10019, (212) 315-8700, (212)265-5642, (800) 586-4872, <http://www.lungusa.org/tobacco>.

Office on Smoking and Health National Center for Disease Prevention and Health Promotion Centers for Disease Control and Prevention, (770) 488-5705, (770) 488-5705, <http://www.cdc.gov/tobacco>.

Marianne F. O'Connor, MT, MPH