Dr. Neal Benowitz helps us to understand nicotine addiction in a recently published review article in The New England Journal of Medicine about the Mechanisms of Disease/Nicotine Addiction. He has examined nicotine as a determinant of addiction to tobacco and the pharmacologic effects of nicotine that sustain cigarette smoking. Cigarette smoking remains a leading cause of preventable disease and premature death in the United States and other countries. Tobacco addiction (like all drug addictions) involves the interplay of pharmacology, learned or conditioned factors, genetics, and social and environmental factors (including tobacco product design and marketing). The pharmacologic reasons for nicotine use are enhancement of mood, either directly or through relief of withdrawal symptoms, and augmentation of mental or physical functions.

Nicotine sustains tobacco addiction, a major cause of disability and premature death, by acting on nicotinic cholinergic receptors in the brain to trigger the release of dopamine and other neurotransmitters. Release of dopamine, glutamate, and GABA is particularly important in the development of nicotine dependence, and CRF may play a key role in withdrawal.

Neuroadaptation and tolerance involve changes in nicotinic receptors and neural plasticity. Nicotine addiction occurs when smokers come to rely on smoking to modulate mood and arousal, relieve withdrawal symptoms, or both. Light or occasional smokers smoke mainly for positive reinforcement in specific situations.

Genetic studies indicate that nicotinic receptor subtypes and the genes involved in neuroplasticity and learning play a part in the development of dependence. People with psychiatric or substance-abuse disorders, who account for a large proportion of current smokers, have an increased susceptibility to tobacco addiction.

Nicotine is metabolized primarily by the enzyme CYP2A6, and variation in the rate of nicotine metabolism contributes to differences in vulnerability to tobacco dependence and the response to smoking-cessation treatment. An increased understanding of the mechanisms of nicotine addiction has led to the development of novel medications (e.g., varenicline) that act on specific nicotinic receptor subtypes. The development of other drugs that act on nicotinic receptors and other mediators of nicotine addiction is likely to further enhance the effectiveness of smoking-cessation pharmacotherapy.

On average, 435,000 people in the United States die prematurely from smoking-related diseases each year; overall, smoking causes 1 in 5 deaths. The chance that a lifelong smoker will die prematurely from a complication of smoking is approximately 50%.

Tobacco use is a major cause of death from cancer, cardiovascular disease, and pulmonary disease. Cigarette smoking is also a risk factor for respiratory tract and other infections, osteoporosis, reproductive disorders, adverse postoperative events and delayed wound healing, duodenal and gastric ulcers, and diabetes. In addition, smoking has a strong association with fire-related and trauma-related injuries. Smoking-caused disease is a consequence of exposure to toxins in tobacco smoke. Although nicotine plays a minor role, if any, in causing smoking-induced diseases, addiction to nicotine is the proximate cause of these diseases.

Currently, about 45 million Americans smoke tobacco. Seventy percent of smokers say they would like to quit, and every year, 40% do quit for at least 1 day. Some highly addicted smokers make serious attempts to quit but are able to stop only for a few hours. Moreover, the 80% who attempt to quit on their own return to smoking within a month, and each year, only 3% of smokers quit successfully. Unfortunately, the rate at which persons — primarily children and adolescents —become daily smokers nearly matches the quit rate, so the prevalence of cigarette smoking has declined only very slowly in recent years.

Click on this link for a copy of the complete reprint.