Approximately one in every five deaths in the United States is due to complications related to smoking. The harmful effects of smoking are due to several factors, including the smoke from nicotine. Nicotine is a basic alkaloid, or a naturally occurring chemical, that has strong psychological effects.

Predisposition to Nicotine Dependence
Nicotine is metabolized by liver enzymes called CYP2A6, CYP2B6 and CYP2E1. It is converted into a substance called cotinine. There are several different forms of CYP2A6, which is the predominant metabolizer of nicotine. Different forms metabolize nicotine at different rates. The concentration of the forms differs between races and sexes, causing different races to breakdown and remove nicotine at different rates. Caucasians and Hispanics breakdown nicotine more slowly than African Americans and Asians. Women also metabolize nicotine faster than men, especially women taking hormonal oral contraceptives or during pregnancy.

Individuals that breakdown nicotine more quickly often smoke more in order to maintain the same level and effect of nicotine as those that break it down slower. Thus, those that metabolize nicotine more slowly are less dependent on cigarettes and can quit more easily than fast metabolizers. The half-life of nicotine is approximately 2 hrs.

Comorbidity with psychological disorders
Several psychological disorders are associated with addiction. Almost half of cigarettes in the U.S. are sold to individuals with mental disorders even though only 22% of the population have a mental illness. Smoking is particularly common among individuals that have the following disorders:

• Schizophrenia
• Major depression
• Manic-depressive disorder
• Anxiety disorder
• Panic attacks
• Attention deficit disorder
• Posttraumatic stress disorder
• Alcohol abuse
• Illegal drug abuse

These individuals are also more likely to experience stronger withdrawal symptoms, particularly those with depression. The link between nicotine addiction and these disorders is likely due to the similarity in altered genetics that leaves the individual vulnerable to each condition.

The negative health effects of smoking on individuals with mental illnesses are even greater than they are for others. Individuals with mental illness are likely to die 25 years earlier due to heart disease and diabetes. These conditions are often made worse by smoking.

Nicotine Addiction
Nicotine is one of the most addictive substances available. It is as addictive as illegal drugs such as cocaine and heroin. Nicotine increases the levels of dopamine in the brain. Dopamine generates a pleasure response, reinforcing the act of nicotine ingestion. Nicotine also increases the pleasure experienced from other stimuli. During nicotine withdrawal, there is a decrease in this reward response. Other negative effects are experienced during withdrawal such as depressed mood and irritability. The combination of the pleasure experienced while ingesting nicotine and avoidance of nicotine withdrawal symptoms are the primary driving force behind continued nicotine use.

Environmental cues also contribute to nicotine dependence. Certain stimuli can be associated with the positive effects of nicotine or with the withdrawal symptoms causing the user to seek out nicotine use. For example, if the user normally smokes when out with friends, drinking alcohol, or after eating a meal, these activities can trigger the euphoric feeling of nicotine and urge to smoke. Even feelings similar to nicotine withdrawal that the user previously treated with smoking may trigger the urge to smoke. These include feelings of stress, anxiety, or irritability due to non-nicotine related events.

Genetics underlying addiction
Due to the fact that different types of nicotine metabolizing enzymes can affect the ability to quit smoking, it is no surprise that nicotine addiction and the ability to quit can be inherited. Withdrawal symptoms experienced while quitting can also be inherited.

A study comparing smokers that became addicted and those that did not found that there were several differences in gene expression between the two groups including nicotine receptor genes, neurexin 1 (helps hold synapse between communicating cells together), VPS13A (vacuolar sorting protein), KCNJ6 ( a potassium channel), and the GABA A4 receptor gene. These genes are involved in many different functions related to cell communication, which supports the theory that drug use alters cell signaling and communication.