Nicotine dependence

Smoking remains the leading cause of preventable death worldwide. It consists of a multistage process, for which nicotine dependence is the limiting phase of smoking cessation, characterized by a compulsive desire to smoke and loss of control over consumption despite the consequences.

Nicotine dependence is defined as an adaptation to repeated nicotine exposure manifested by compulsive use, the development of tolerance, the experience of withdrawal symptoms upon cessation of nicotine use, and the inability to quit despite the harmful effects. Nicotine dependence develops as the person maintains nicotine use, most often as cigarettes, but also others such as chewing tobacco or pipes, including the use of electronic cigarettes.

Nicotine is a parasympathetic stimulant that binds to nicotinic acetylcholine receptors in the brain and activates them leading to the release of dopamine and other neurotransmitters such as norepinephrine, acetylcholine, serotonin, GABA, or endorphins. In addition, repeated exposure to nicotine increases the number of nicotinic receptors implying higher consumption to achieve the same effects, which is known as tolerance. Chronic activation of nicotinic acetylcholine receptors can induce changes in brain physiology, resulting from stimulation of brain regions associated with reward, pleasure and anxiety, altering the normal functioning of these circuits. Thus, when these receptors are not occupied, withdrawal symptoms such as cravings, irritability, anxiety, depression, impatience, sleep problems, restlessness, hunger, or difficulty concentrating are triggered. In addition, there are other changes that occur as dependence develops, since cigarette smoking is psychologically linked to certain moods and social contexts.

According to the World Health Organization, it has been shown that greater nicotine dependence is associated with less motivation to quit smoking, difficulty in trying to quit and failure in the attempt, as well as smoking the first cigarette earlier in the day and smoking more cigarettes per day. Additionally, it has been established that there is a higher frequency of nicotine dependence in people with anxiety disorders due to the existing psychosocial link.

The nicotine dependence stage of smoking, which follows regular smoking, has a strong genetic component. A GWAS study of 58,000 individuals has identified 6 loci distributed in different genes that influence this stage of smoking.

Number of observed variants

13.5 million variants

Number of loci analyzed in the study

6 loci


Wittenberg RE et al. Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology 2020;177:108256.

Mayo Clinic. Nicotine dependence. [May 2022]

National Institute on Drug abuse. Tobacco, Nicotine, and E-Cigarettes Research Report [May 2022]

Quach BC et al. Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits. Nature Communications, 03 Nov 2020, 11(1):5562.

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