Nicotine

At the beginning of the twentieth century, lung cancer was a rare medical disease. The "cigarette," a new product, was becoming popular among the wealthy and trendsetters, while in England, Professor John N. Langley of Cambridge University was exploring the effects of nicotine, a powerful chemical and effective pesticide extracted from tobacco. It was known that nicotine could be absorbed through the skin, causing sickness in humans. Understanding of how the brain and nervous system work (called "neuroscience" today) was just emerging at the beginning of the century. Little was known about the functioning of the brain or how it sent messages through the body's network of nerve fibers to move muscles or stimulate the heart, or how these nerves transmitted information to the brain. Nicotine would become one of the chemicals used to help unravel these mysteries and jumpstart the field of neurophysiology.

By the end of the twentieth century, a groundswell of scientific research had transformed our understanding of nicotine from being an obscure poison to being an addicting drug responsible for taking millions of tobacco smokers to premature death. Many secrets of the brain and nervous system were also unraveled through the help of nicotine, because nicotine has profound effects on parts of the nervous system (now termed "nicotinic"). Thus, nicotine emerged as a vital laboratory tool in understanding the functioning of the nervous system. From the standpoint of public health, one of the most striking features in the history of nicotine science was the recognition that nicotine was an addicting drug, and that tobacco addiction was among the deadliest addictions in the world. Nearly one-half of daily smokers would die prematurely of tobacco-attributed diseases—primarily cancer, lung, and cardiovascular diseases.

What led to the development and understanding of nicotine as a deadly drug? How does nicotine affect the nervous system, and what role does it play in tobacco use? These are some of the vexing questions that scientists around the world grappled with as they learned about nicotine and its effects on the body.

History of Nicotine

Nicotine derives its name from Jean Nicot, a French ambassador to the Portuguese court from 1559 to 1561. The story is that the thirty-yearold diplomat paid a visit to a famous Portuguese horticulturalist, Damiao de Goes, who gave him leaves from a strange plant reputed to have marvelous effects. Nicot dried the leaves, crushed them, and sent the powder back to the queen mother Catherine de Medici, who suffered from severe headaches. Reportedly, the remedy worked, and the tobacco plant quickly gained popularity in France, making Nicot something of a celebrity. The plant came to be called the Herb of Nicot.

But it was not until the nineteenth century that the chemical nicotine was identified as a distinct ingredient in tobacco. In 1809, Louis Nicolas Vauquelin (a French chemist) extracted a "potent, volatile, and colorless substance" from tobacco which he named essence de tabac, though it was not pure nicotine that was derived. In 1828 two chemistry students at the University of Heidelberg, Ludwig Reimann and Wilhelm Heinrich Posselt, first isolated nicotine, which they named after Nicot, as the active ingredient in tobacco.

In 1905, John Newport Langley, a British physiologist, discovered that a miniscule drop of nicotine stimulated muscle fibers while a similar amount of another poison, curare, paralyzed them when administered simultaneously to anesthetized birds. Langley correctly concluded that muscles and nerves must contain what he termed "receptive substances" (now called "receptors"). In response to different chemicals, these receptors were either activated or deactivated. Drugs that activate receptors are called "agonists." For example, the deadly poison, curare, exerted its lethal paralysis of muscles, including those working the lungs, by blocking nicotinic receptors. But the right dose of nicotine could reactivate muscles depressed by curare. Nicotine was one of a particularly interesting type of chemicals in which a small amount (called the "dose") could produce activation while a larger dose could produce deactivation. In other words, the strength of nicotine's effects was closely related to the dose administered and repeated dosing led to weaker effects (or tolerance). These discoveries helped to explain how muscles could be stimulated or relaxed by the same nerve. By the end of the twentieth century, thousands more of the body's receptor types and subtypes had been identified, helping to explain many aspects of physical, behavioral, and cognitive functioning. This led to the discovery of medicines for treating hundreds of diseases.

Nicotine's Effect on the Body

Nicotine is the cerebrally acting drug in tobacco that defines its addicting effects, similar to the way cocaine in the coca leaf and morphine in the opium poppy define the addictive effects of those substances. Nicotine affects the brain by binding to specific receptors (called nicotine cholinergic receptors) on the surface of brain cells. This stimulates the cells to release neurotransmitters such as epinephrine and dopamine. Epinephrine provides the fast "kick" to the smoker, causing a release of glucose and an increase in heart rate, blood pressure, and breathing. Dopamine is fundamental to reward and pleasure pathways in the brain and is boosted by other addictive drugs, such as cocaine and heroin, as well as by nicotine.

Nicotine produces an entire range of physical and behavioral effects characteristic of addicting drugs. These effects include activation of brain reward systems (creating behavioral effects and physiological cravings that lead to chronic drug use), tolerance and physical dependence, and withdrawal with drug abstinence. Nicotine alters a person's mood, feelings, and behavior, and its effects can be complicated. At very high doses, the effects of nicotine on heart rate and blood pressure can be dangerous, even fatal, but there is no conclusive evidence that modest doses of nicotine—like those received from a nicotine patch—are detrimental to health.

The fast action of inhaled nicotine makes cigarette smoking the most addictive route for administering nicotine, which reaches the smoker's brain less than 10 seconds after inhalation. Because inhaled nicotine reaches the bloodstream so quickly, it produces an intense but short-lived spike in its levels. In contrast, nicotine from a skin patch works its way into the bloodstream slowly, over about three hours, and never reaches the peak levels that inhaled nicotine does, even when the overall dose is the same (nicotine nasal spray and nicotine chewing gum fall somewhere in the middle). Not surprisingly, smokers report that their habit is highly reinforcing (they want to keep repeating the experience), but they do not show the same enthusiasm for the nicotine patch.

Nicotine dependence is far more common than cocaine, heroin, or alcohol dependence following initial use of these drugs. Approximately one-third to one-half of those who try smoking increase to more regular or daily use, and most daily smokers become addicted. In contrast, less than one in four persons who try cocaine or heroin develop addiction, and less than 15 percent of alcohol users develop addiction. Nicotine, alone and in combination with other substances, appears to help regular smokers control their mood and body weight and maintain attention when working. Daily smokers will claim that they function best on nicotine. Even a brief period of tobacco abstinence can leave some addicted individuals unable to complete their office- or schoolwork, or to perform adequately.

Tobacco Product Design

Nicotine accounts for approximately 1–4 percent of the weight of a typical tobacco leaf, which is transferred into the bloodstream by chewing products made for oral use or by inhaling the smoke of burning tobacco. Tobacco products can be viewed as nicotine storage and delivery systems. The tobacco industry has used a variety of techniques to enhance the delivery of nicotine to the user by controlling the nicotine dosing characteristics of cigarettes and other products. The modern cigarette is intricately designed, involving numerous patents for cigarette wrappers, filter systems, and processes for making "tobacco filler" from tobacco materials and other substances. William Dunn, a senior Philip Morris scientist, has eloquently described the cigarette's function:

The cigarette should be conceived not as a product but as a package. The product is nicotine. Think of the cigarette as a dispenser for a dose unit of nicotine. . . . Think of a puff of smoke as the vehicle of nicotine. Smoke is beyond question the most optimized vehicle of nicotine and the cigarette the most optimized dispenser of smoke

(CAMPAIGN FOR TOBACCO-FREE KIDS 1998,
CITED IN HURT AND ROBERTSON).

Tobacco is a complex "cocktail" of more than 4,000 distinct chemical substances, some of which can interact to increase the addicting effects of tobacco-delivered nicotine, far above those produced by nicotine alone. For example, buffering compounds in smokeless tobacco products can alter the speed and amount of nicotine delivered in those products. The addition of menthol apparently allows smokers to inhale larger quantities of smoke, and nicotine, by making them feel less harsh. Techniques are also employed to control the size of smoke particles allowing the efficient inhalation of nicotine deep into the lungs where absorption is rapid and virtually complete. Among the many chemicals in tobacco smoke, scientists are only now beginning to unravel the many individual chemicals and their combinations that bolster the addictive effects of tobacco.

Nicotine Addiction "Drives" Smoking Behavior

While early antitobacco campaigns warned that cigarette smoking could be habit forming, drawing parallels with narcotics, it was not until the 1980s that leading scientists and health organizations recognized cigarettes to be addicting. The 1988 United States Surgeon General's report focused on the role of nicotine in smoking and concluded that "Cigarettes and other forms of tobacco are addicting," "Nicotine is the drug in tobacco that causes addiction," and "The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine."

Smokers become very adept at getting the dose that provides the desired effects. This is associated with a phenomenon known as "tolerance," which refers to increasing the amount of drug to experience the same effects once received at lower doses. When tolerance develops and tobacco intake increases, a person typically becomes physiologically dependent. Quitting is accompanied by withdrawal symptoms, including impaired concentration, irritability, weight gain, depressed mood, anxiety, difficulty sleeping, and persistent craving for a cigarette. During withdrawal, resumption of smoking provides rapid relief of withdrawal effects, leading the smoker to believe that smoking is a mood and performance-enhancing substance. However, resumption of smoking prevents withdrawal that occurs because physical dependence results from daily use of tobacco. Although there is individual variation, withdrawal usually peaks within a few days and subsides within a month.

Nicotine and Public Health

The World Health Organization, the United States Public Health Service, and most major health organizations worldwide endorsed efforts to make tobacco abstinence a major health priority by the end of the twentieth century. The overwhelming weight of scientific study has shown that quitting smoking at virtually any age results in a reduced disease risk and better health outcomes if tobacco-attributed disease has already developed. The results of smoking cessation are quite dramatic. For example, the risk of heart disease—the leading cause of death among smokers—is reduced nearly to that of nonsmokers within one to two years of cessation.

Preventing the development of tobacco addiction is vital to the long-term health of generations to come. But the road to longer and healthier lives is in cessation for today's 50 million cigarette smokers in the United States and more than 1.2 billion smokers worldwide. Therefore, major governments and health organizations have launched important initiatives to motivate people to quit smoking. In recognition of the power of addiction and the need for people to quit, these organizations have also made smoking cessation treatments more accessible. Many people can now receive medical assistance to achieve freedom from tobacco by contacting the public health service of their nation, cancer institutes, the World Health Organization, and various voluntary organizations such as local cancer societies and lung health organizations.

See Also Addiction; Genetic Modification; "Light" and Filtered Cigarettes; Toxins.

? PATRICIA B. SANTORA
? JACK E. HENNINGFIELD

BIBLIOGRAPHY

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opium an addictive narcotic drug produced from poppies. Derivatives include heroin, morphine, and codeine.

epinephrine also called adrenaline, a chemical secretion of the adrenal gland. Epinephrine speeds the heart rate and respiration.

dopamine a chemical in the brain associated with pleasure and well-being. Nicotine raises dopamine levels and intensifies addiction to cigarette smoking.

physiology the study of the functions and processes of the body.

menthol a form of alcohol imparting a mint flavor to some cigarettes.