This is a psychoactive chemical substance found in tobacco products, including cigarettes, cigars, pipe tobacco, and smokeless tobacco such as chewing (spit) tobacco and oral and nasal snuff. The nicotine molecule is composed of a pyridine ring (a 6-membered nitrogen-containing ring) with a pyrrolidine ring (a 5-membered nitrogen-containing ring).
Nicotine can occur in two forms. The active form, called L-nicotine, is found in tobacco plants of the genus Nicotiana. These are chiefly South
American plants of the nightshade family (Solanaceae)—annuals cultivated since pre-Columbian times for their leaves, especially Nicotiana tabacum. The inactive form, D-nicotine, is not present in tobacco leaves but is formed, to a small extent, in the combustion of tobacco during smoking. These two forms are stereoisomers, meaning that even though they are both nicotine, they have different three-dimensional structures. In pure form, nicotine is a colorless liquid, but it turns brown on exposure to air.
Nicotine is water-soluble and transfers from tobacco to cigarette smoke readily, because it vaporizes easily. Once it is in the body, conditions are ideal for rapid distribution to blood and tissues because nicotine is a weak base, and when un-ionized under alkaline conditions, such as those found in the blood stream, it crosses cell membranes easily.
The primary natural source of nicotine is the tobacco plant, but nicotine is also found in some amount in related plants. Small amounts are in foods of the nightshade family, such as tomatoes and eggplants. Consumption of nicotine has not been limited to the use of plants in which it naturally occurs. In 1828, the German scientists Posselt and Reiman isolated nicotine from tobacco leaves, and since then it has been added to other products. For example, it is widely used as an insecticide in such products as Black Leaf 40, which contains 40 percent nicotine sulfate.
EFFECTS OF NICOTINE
The first pharmacological studies of nicotine were initiated in 1843 by Orfila. Nicotine is an alkaloid that affects major organs, such as the heart and brain. It also affects the body at the cellular level.
Effects in the Body. The actions of nicotine in a human body are complex. They depend on the amount of nicotine given, the route of administration (e.g., by mouth or intravenously), the time over which the dose is given, and the individual's history of exposure to nicotine. In high doses, nicotine produces nausea, vomiting, convulsions, muscle paralysis, cessation of breathing, coma, and circulatory collapse. Such high doses are seen after accidental absorption of a nicotine-containing insecticide or an overdose of nicotine.
In lower doses, such as those used by people who consume tobacco products, the effects are very different. They include a speed up in heart rate and blood pressure; increased force of contraction of the heart; constriction of blood vessels in the skin, producing cool, pale skin; constriction of blood vessels in the heart; relaxation of skeletal muscles; increased body metabolic rate; and the release of hormones such as epinephrine (adrenaline), norepinephrine, and cortisol into the bloodstream. Nicotine's effects on the brain are very complex because nicotine works in part by enhancing the release of chemicals that transmit information from one neuron to another (neurotransmitters) by brain cells. For example, nicotine enhances the release of dopamine, which may produce pleasure; norepinephrine, which may suppress appetite; acetylcholine, which produces arousal; serotonin, which may reduce anxiety; and beta endorphin, which may reduce pain. The development of addiction to nicotine in tobacco users is attributed in part to many of the effects of nicotine that people find desirable.
Effects of Nicotine in Cells. Nicotine binds (attaches) to receptors on cell membranes that normally bind a neurotransmitter called acetylcholine. Acetylcholine, like other neurotransmitters, is a chemical released by nerve endings in the body that binds to certain receptors on cells and activates them. The activated cells communicate messages to other nerves or produce specific actions on body organs. Nicotine activates only certain of the receptors that bind acetylcholine. These receptors are now called nicotinic cholinergic receptors. Using the selective action of nicotine on cholinergic receptors, scientists are able to observe their activity separately from muscarinic cholinergic receptors, receptors activated by a chemical called muscarine. Page 136 | Top of ArticleNicotinic cholinergic receptors are located at the ganglia in the autonomic nervous system, where there are specialized areas for communications between nerves, in the adrenal gland, at the neuro-muscular junctions, where nerves attach to and activate muscles, and in many parts of the brain.
The greatest number of nicotine cholinergic receptors in the brain are found in the hypothalamus, hippocampus, thalamus, midbrain, brain stem, and many parts of the cerebral cortex. Nicotine acts on sensory receptors, including those that mediate pain sensations. The effects of nicotine on these specific receptors have been an important tool in studying the effects of neurotransmitters on cell receptors and on the nervous system as a whole. In addition, these studies provide information about the widespread effects of nicotine introduced into the body during tobacco use.
DEVELOPMENT OF PHYSICAL DEPENDENCE ON NICOTINE
Nicotine is the chemical substance responsible for physical dependence on tobacco products. During the development of physical dependence on a drug such as nicotine, brain chemistry and function change. They return to normal in the presence of nicotine and come to depend on the drug for normal function.
The change that results in normal function in the presence of nicotine is called neuroadaptation or tolerance. When tolerance develops after a period of use of nicotine, or of any drug, the same dose produces less of an effect than previously. Tolerance develops to many of the effects of nicotine. It is well-known that people smoking their first cigarette often experience nausea and vomiting. However, after repeated exposure to cigarette smoke, these effects disappear. Their disappearance is the development of tolerance to the toxic effects of nicotine in the cigarette smoke. Tolerance also develops to the more desirable effects of nicotine such as pleasure and alertness.
The development of tolerance is associated with changes in the brain, such as an increased number of nicotinic cholinergic receptors found in the brains of smokers studied at autopsy. The changes in the brain correspond to a state in which the tolerant brain comes to depend on nicotine for normal functioning. This state is called physical dependence.
Physical dependence also means that abstinence or withdrawal symptoms occur when a person who has taken a drug on a regular basis stops taking it. Physical dependence on nicotine has been clearly demonstrated. Thus a person who stops using tobacco after his or her body has adapted to the presence of nicotine will experience withdrawal symptoms in the form of irritability, restlessness, drowsiness, difficulty concentrating, impaired job performance, anxiety, hunger, weight gain, sleep disturbances, slow down in heart rate, and a strong urge for nicotine. In general, withdrawal symptoms are opposite to the effects produced by nicotine when a person who is not tolerant uses it. Thus a person will start using tobacco primarily to experience the desired effects of nicotine, but once the addiction develops, use of tobacco may be chiefly to prevent the emergence of unpleasant withdrawal symptoms. Use of a drug to prevent withdrawal is common in people who are addicted to a drug.
ABSORPTION OF NICOTINE FROM TOBACCO
Nicotine, which is absorbed into the body when tobacco products are used, can be absorbed by different routes and at different rates. Some products deliver nicotine in smoke that is inhaled. In tobacco smoke, nicotine is present in droplets that also contain water and tar. These droplets are carried by gases that include carbon monoxide, hydrogen cyanide, and nitrogen oxides. Such suspended droplets carried by gas are called an aerosol. When the aerosol is inhaled, the droplets are deposited in the small airways of the lungs, from which nicotine is absorbed into the blood stream. After absorption through the lungs, blood containing nicotine moves into the heart and then into the arterial circulation, including the brain. Nicotine reaches the brain within 10 to 15 seconds after a puff on a cigarette. This rapid delivery of nicotine to the brain produces more intensive effects than following slower delivery and provides the close temporal link between smoking and the development of addiction.
Nicotine is absorbed into the body in other ways. It can be absorbed in the mouth even if not inhaled in pipe or cigar smoke. In addition, not all Page 137 | Top of Articletobacco products deliver nicotine through smoke. Chewing tobacco consists of shredded tobacco or plugs of tobacco that are enhanced with licorice and other flavorings. These products are periodically chewed, and the saliva generated is spat out, hence the term spit tobacco. Oral snuff is finely cut tobacco. A portion of oral snuff, called a pinch, is placed between the lip and the gum. Nicotine is absorbed from these forms of tobacco more slowly than from inhaled smoke, but the total amount absorbed is similar. Nasal snuff is finely powdered tobacco that is sniffed into the nose, where nicotine is rapidly absorbed.
DOSES OF NICOTINE TAKEN IN TOBACCO
The dose of nicotine absorbed from a cigarette is on average about 1 milligram (mg). The average user smokes about 25 cigarettes a day, an average nicotine intake of 20 to 30 mg daily. The average amount of nicotine absorbed from chewing tobacco or snuff per day is similar to that obtained from cigarettes. A person who smokes 25 cigarettes a day will absorb about 200 grams of nicotine in 20 years of smoking.
Nicotine is available as a medication, used to assist people in quitting smoking. These medications are meant to provide nicotine to smokers as a substitute for nicotine formerly consumed from tobacco use. Nicotine medications reduce withdrawal symptoms and increase the likelihood that the individual will quit tobacco use. Two forms of nicotine medication are currently available. Nicotine chewing gum (nicotine polacrilex, also known as Nicorette) consists of nicotine in a gum that slowly releases nicotine during chewing. Each gum is typically chewed for about 30 minutes. People chew up to 16 pieces per day when trying to quit smoking.
Nicotine patches are applied to the skin. They release nicotine slowly through the skin over 16 or 24 hours, depending on the patch used.
Both forms of nicotine-replacement medication deliver doses of nicotine equivalent to that taken in by the average tobacco user. Nicotine chewing gum delivers about 1 to 2 mg per piece. Nicotine patches deliver from 5 to 21 mg, depending on the patch and its strength.
ELIMINATION OF NICOTINE FROM THE BODY
Nicotine in the body is eliminated primarily by breakdown by the liver. The rate of breakdown is such that the level of nicotine in the blood falls about one-half after two hours. This rate is also known as a half-life of two hours. The primary breakdown product of nicotine is cotinine. Coti-nine levels in the body are about 10 times higher than those of nicotine. The half-life of cotinine is 16 hours, and cotinine persists in the body for 4 days after a person stops smoking. Cotinine levels can be measured as an indicator of how much nicotine a person is taking in.
Addiction to nicotine is well documented. The development and characteristics of nicotine addiction are described in detail in a report from the U.S. Surgeon General published in 1988. In this report, The Health Consequences of Smoking: Nicotine Addiction, the surgeon general presents criteria for nicotine addiction including the following:
- Highly controlled or compulsive use. Smokers have great difficulty abstaining. Seventy percent of the 45 million smokers in the United States today report that they would like to quit and can not.
- Psychoactive effects. Nicotine, as described earlier in this article, has pronounced effects on the brain.
- Drug-reinforced behavior. Tobacco use is motivated by a desire for the effects of nicotine. People do not smoke cigarettes that do not contain nicotine. Very few people choose to smoke cigarettes that deliver very low doses of nicotine.
Other factors lead to the conclusion that nicotine is addictive:
- It is used despite harmful effects. Most people know that smoking is harmful to their health and continue to smoke. Many people who have nicotine-related diseases are still unable to quit.
- Relapse following abstinence. Most smokers can quit for a few days or even weeks (abstinence), but most of these smokers return to smoking within a month. Typically, it takesPage 138 | Top of Articlefour or five attempts before a smoker is successful at quitting permanently.
- Recurrent drug cravings. Most smokers have an intense craving or urge to smoke when they have not smoked for some period of time.
- Physical dependence
- Pleasurable effects
The last three factors were described previously.
Smokers carefully regulate nicotine intake to maintain desired levels of nicotine in the body. Such careful regulation is further evidence that nicotine is addictive. Smokers keep the amount of nicotine obtained from cigarettes constant in two ways.
- When people are given cigarettes that are labeled as low-yield (see tobacco history for detailed discussions of yields), they smoke more intensively to obtain the same dose of nicotine they were used to obtaining from the higher-yield cigarettes.
- When they are forced to cut down on the number of cigarettes they smoke each day, they will take in more nicotine per cigarette. Thus when smoking is restricted, smokers tend to maintain the nicotine in their bodies at close to levels maintained during unrestricted nicotine intake.
BEHAVIORAL ASPECTS OF TOBACCO ADDICTION
People continue to smoke both because they enjoy the direct drug effects of nicotine and because use of nicotine becomes associated with other pleasures through learning—for instance, when the pleasurable effects of nicotine occur repeatedly in the presence of specific cues or events in the environment. Eventually, those cues and events become a signal to smoke. For example, people often smoke after meals, while drinking a cup of coffee or an alcoholic beverage, during a break from work, while talking on the phone, or while with friends who smoke. After smoking in these situations hundreds of times, the user may find that these situations themselves produce a powerful urge for a cigarette.
There are other learned pleasures that keep people smoking independent of the pharmacological effects of nicotine. Handling of smoking materials, and the taste, smell, or feel of tobacco smoke in the throat, all can become associated with the effects of nicotine and then become pleasurable in themselves. A person who tries to quit must learn to give up not only the pharmacological actions of nicotine but also the aspects of smoking that have become pleasurable through learning. Urges aroused after learning an association between aspects of the environment and the pleasures of smoking prompt relapses in many people who have already overcome withdrawal from nicotine and quit tobacco use.
Smokers report many other reasons for their habit. For example, many smokers, particularly women, smoke to maintain lower body weight. Others seem to use tobacco to control mood disturbances, such as depression or anxiety.
COMPARISON OF ADDICTION TO NICOTINE AND OTHER DRUGS
Nicotine addiction is similar to and as powerful as addiction to other drugs, such as heroin, alcohol, and cocaine. All these drugs have psychoactivity and produce pleasure. They increase the likelihood that people will spend time looking for them and engaging in rituals while taking them and that users will continue to take them in the face of risk to their well-being and health. The psychoactivity of nicotine is subtle and does not interfere with normal functioning in daily life. Thus nicotine's psychoactivity differs from that of heroin and cocaine, which produces more intense euphoria and may be disruptive to everyday functioning. Despite this difference, nicotine is addictive. A subtle psycho-active effect, especially when experienced with each puff of smoke, taken hundreds of times a day, exerts a powerful effect on behavior over time. The magnitude of effect becomes apparent when each puff of cigarette is considered as a dose of nicotine. A smoker who takes 8 puffs per cigarette and smokes 20 cigarettes per day is receiving up to 160 doses of nicotine per day. The dosing is equivalent to 58,400 doses a year, or 1,168,000 doses after 20 years of smoking.
When difficulty in quitting and relapse after attempting to quit are compared, it becomes apparent that nicotine is even more addictive than other drugs of abuse. Ninety percent of all people who smoke cigarettes are addicted and have difficulty quitting. In contrast, only about 10 percent Page 139 | Top of Articleof people who drink alcohol at all have difficulty controlling use and would be classified as addicted. The percentage of occasional versus addicted users of heroin and cocaine is not known, but when multidrug users are asked about which drug they would have most difficulty giving up, the choice is most commonly nicotine (that is, cigarettes). Relapse rates among adults after cessation of alcohol, heroin, and tobacco use are similar.
NICOTINE ADDICTION IN YOUTH
Ninety percent of all tobacco users begin smoking before the age of 20. The earlier in life one starts smoking, the more likely he or she is to become a regular smoker and the more cigarettes he or she will smoke as an adult. The development of addiction in youth involves a series of steps including
- a trying stage
- regular smoking
- nicotine addiction
The typical interval between trying and addiction is 2 to 3 years.
Initially, young people smoke for social and psychological reasons. The motivations include the influence of parents and friends who are smokers, and the positive images of smoking perpetuated in television and movies and in advertisements in magazines, at music and sports events, and on billboards. Personal factors also play a role. Some include poor school performance, low self-esteem, poor self-image, sensation seeking, rebelliousness, failure to take seriously the adverse effects of tobacco use, and depression or anxiety. While early stages of smoking usually consist of occasional sessions with friends, tolerance develops and withdrawal symptoms are experienced between cigarettes as smoking becomes more frequent. Many youths report withdrawal symptoms and difficulty quitting. They consider themselves addicted to tobacco.
TREATMENT OF NICOTINE ADDICTION
Treatment of nicotine addiction is discussed in the articles entitled Treatment: Tobacco. The approach may be summarized as follows. Initial therapy usually does not include drugs. Smokers are encouraged to pick a day and just stop (go cold turkey). Some smokers participate in formal behavioral therapies, such as those available in smoking-cessation clinics. Those who are unable to stop on their own or with behavior therapies are more likely to be highly addicted to nicotine and are candidates for pharmacological (drug) therapy. The main drug therapies for smoking are nicotine-containing medications such as chewing gum or transdermal (skin) patches.
See also Addiction: Concepts and Definitions; Adolescents and Drug Use; Reward Pathways and Drugs; Tobacco: Smokeless; Tolerance and Physical Dependence; Withdrawal: Nicotine (Tobacco).
Benowitz, N. L. (1988). Pharmacologic aspects of cigarette smoking and nicotine addiction. New England Journal of Medicine, 319, 1318–1330.
George, T. P. (2006). Medication treatments for nicotine dependence. Boca Raton, FL: CRC Press.
Maldonado, R. (2003). Molecular biology of drug addiction. Totowa, NJ: Humana Press.
Naff, C. F. (2007). Nicotine and tobacco. San Diego, CA: Reference Point Press.
Novartis Foundation. (2006). Understanding nicotine and tobacco addiction. Hoboken, NJ: Wiley.
U.S. Surgeon General. (1988). The health consequences of smoking: Nicotine addiction. Washington, D.C.: U.S. Government Printing Office.
NEAL L. BENOWITZ
ALICE B. FREDERICKS