Nicotine Addiction and Withdrawal

Nicotine releases dopamine in the brain's reward circuit, and with repeated use the receptors multiply and adapt, which is what makes stopping hard. This page collects the published research on nicotine dependence, withdrawal and quitting, each paper summarised in plain language with its PubMed record.

This collection is research only: papers found on PubMed, each described as its own abstract reports it. Cell and animal results are labelled as such, and harms are listed beside benefits. It is not medical advice.

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The Papers (26)

Newest first. Study types on this page — Human observational study: 3 · Review: 21 · Animal study: 2. Each summary is written from the paper’s own abstract; follow the PubMed link for the full record.

Addiction-related neuroadaptations following chronic nicotine exposure

Review, 2021. This review describes how nicotine acts on nicotinic receptors in the brain to produce both reward and aversion, mostly drawing on research in animals. Receptors on dopamine nerve cells in a midbrain area called the ventral tegmental area drive nicotine's reward effects. Receptors in two other areas, the medial habenula and the interpeduncular nucleus, set the point at which nicotine becomes unpleasant and help control how much is taken in. The authors explain that repeated exposure changes these reward and aversion circuits, and that genetic differences in how sensitive they are can affect whether tobacco use moves from occasional to habitual.

Wills L, Kenny PJ (2021). Addiction-related neuroadaptations following chronic nicotine exposure. J Neurochem. — PubMed PMID: 33742685 · doi:10.1111/jnc.15356

Smoking-induced craving relief relates to increased DLPFC-striatal coupling in nicotine-dependent women

Human observational study, 2021. Researchers scanned the brains of 24 nicotine-dependent women who had not been abstaining from smoking. Each woman had a resting brain scan (fMRI) before and after smoking a cigarette inside the scanner, and rated her craving each time. Smoking lowered craving. Women whose craving dropped more also showed stronger communication between a front part of the brain involved in decision-making (the dorsolateral prefrontal cortex) and the striatum, a deeper area that drives motivation and reward. The authors suggest this connection is part of how craving works in the brain.

Franklin TR, Jagannathan K, Spilka NH et al. (2021). Smoking-induced craving relief relates to increased DLPFC-striatal coupling in nicotine-dependent women. Drug Alcohol Depend. — PubMed PMID: 33611027 · doi:10.1016/j.drugalcdep.2021.108593

The modulatory role of nicotine on cognitive and non-cognitive functions

Review, 2019. This review looks at how nicotine affects thinking and other brain functions in both people and animals, including reward, addiction, learning and memory, anxiety, pain, body weight and body temperature. Nicotine works by switching on nicotinic acetylcholine receptors, which are found throughout the nervous system. The authors explain that the brain's dopamine reward system, along with areas such as the hippocampus and amygdala, carries many of these effects. They also describe how other brain chemical systems, including opioid, glutamate, cannabinoid, GABA, serotonin and nitric oxide signaling, help shape nicotine's effects.

Zarrindast MR, Khakpai F (2019). The modulatory role of nicotine on cognitive and non-cognitive functions. Brain Res. — PubMed PMID: 30529105 · doi:10.1016/j.brainres.2018.12.002

Chronic nicotine exposure impairs uncertainty modulation on reinforcement learning in anterior cingulate cortex and serotonin system

Human observational study, 2018. This study looked at how long-term nicotine use affects learning from rewards, focusing on a brain area called the anterior cingulate cortex. In smokers, this brain area did not adjust its learning signals to how uncertain the situation was, and the size of this effect was linked to how fast they learned and how long they had used nicotine. In a second experiment, rats given nicotine had lower activity of serotonin receptor genes, but not dopamine receptor genes, in this brain area than control rats, and that receptor activity was linked to how fast they learned. The authors suggest this impairment may contribute to poor decision-making in chronic nicotine users and point to the serotonin system as a possible target for addiction treatment.

Wei Z, Han L, Zhong X et al. (2018). Chronic nicotine exposure impairs uncertainty modulation on reinforcement learning in anterior cingulate cortex and serotonin system. Neuroimage. — PubMed PMID: 29221752 · doi:10.1016/j.neuroimage.2017.11.048

The Past, Present, and Future of Nicotine Addiction Therapy

Review, 2016. This review looks at the evidence on treatments that help people quit tobacco. It covers medicines used together or for longer periods, and support methods such as advice from a health provider, one-on-one counseling, group programs, the national quitline, websites and social media, and rewards for quitting. The authors note that healthcare policies are changing so that more smokers are offered treatment to quit. They also describe where they expect quit-smoking treatment and public health efforts to go next, including more personalized care and new technology that gives support in real time.

Prochaska JJ, Benowitz NL (2016). The Past, Present, and Future of Nicotine Addiction Therapy. Annu Rev Med. — PubMed PMID: 26332005 · doi:10.1146/annurev-med-111314-033712

Successful Nicotine Intake in Medical Assisted Use of E-Cigarettes: A Pilot Study

Human observational study, 2015. This eight-month pilot study followed adult smokers who began using an e-cigarette after a medically supervised training program with behavioral support, and their nicotine intake was monitored through blood levels of nicotine breakdown products (cotinine and trans-3'-hydroxycotinine). At the end of the first, fourth and eighth months, 91.1, 73.5 and 76.5% of participants were still using the e-cigarette, either alone or alongside regular cigarettes. Their nicotine breakdown-product levels did not change significantly from when they smoked only tobacco cigarettes, while carbon monoxide in their breath, a marker of burning tobacco, fell significantly. The authors report that participants did not have the typical cigarette cravings or signs of nicotine overdose.

Pacifici R, Pichini S, Graziano S et al. (2015). Successful Nicotine Intake in Medical Assisted Use of E-Cigarettes: A Pilot Study. Int J Environ Res Public Health. — PubMed PMID: 26184244 · doi:10.3390/ijerph120707638

Nicotine withdrawal

Review, 2015. This review describes nicotine withdrawal, an unpleasant set of symptoms that begins 4 to 24 hours after a person stops long-term use of nicotine-containing products. Symptoms peak around the third day and fade over the next 3 to 4 weeks. How severe they are depends mostly on how the nicotine was taken, and certain small genetic differences are linked both to heavier nicotine use and to worse withdrawal when trying to quit. Studies in rodents, including genetically modified mice, show that particular nicotinic receptor subunits and brain circuits drive withdrawal symptoms, and the authors suggest that mapping these could lead to more personalized treatments for nicotine addiction.

McLaughlin I, Dani JA, De Biasi M (2015). Nicotine withdrawal. Curr Top Behav Neurosci. — PubMed PMID: 25638335 · doi:10.1007/978-3-319-13482-6_4

Nicotine vapor inhalation escalates nicotine self-administration

Animal study, 2014. This study was done in male rats, not people. Rats that had learned to give themselves nicotine were then exposed to nicotine vapor for 12 hours a day, and afterwards they took about 200% more nicotine than they had at the start and about 3 times more than rats that were not dependent. A second experiment showed that rats taken off the vapor for eight hours had clear physical withdrawal signs when given a drug that blocks nicotine's receptors. The researchers say the air-nicotine levels used were similar to what human smokers are exposed to, and they conclude that repeated, on-and-off nicotine vapor exposure produces both physical and motivational signs of nicotine dependence in rats.

Gilpin NW, Whitaker AM, Baynes B et al. (2014). Nicotine vapor inhalation escalates nicotine self-administration. Addict Biol. — PubMed PMID: 23240929 · doi:10.1111/adb.12021

Nicotine vaccines to treat tobacco dependence

Review, 2013. This review looks at the current state of vaccines against nicotine, which are being tested as a way to treat tobacco addiction. The idea is that the vaccine makes the body produce antibodies that hold on to nicotine in the blood, so less of it reaches the brain. The authors covered vaccines already in clinical trials and others still in early development, along with the problems, challenges and ethical concerns of developing them. The evidence so far shows that nicotine vaccines are well tolerated and do trigger an immune response, but they have not yet been shown to help more people stop smoking.

Goniewicz ML, Delijewski M (2013). Nicotine vaccines to treat tobacco dependence. Hum Vaccin Immunother. — PubMed PMID: 23108361 · doi:10.4161/hv.22060

Modeling nicotine addiction in rats

Review, 2012. This review describes how researchers study nicotine addiction in rats, where the animals can give themselves nicotine through a vein (intravenous self-administration). The authors note that more than 30% of people who try smoking develop a nicotine addiction, compared with 15% of drug users in general who develop a drug addiction. Early attempts to get rats to self-administer nicotine were difficult, but more reliable versions of the method have since been developed. The review covers features of this rat model used to study why nicotine is rewarding and what drives the motivation to keep taking it.

Caille S, Clemens K, Stinus L et al. (2012). Modeling nicotine addiction in rats. Methods Mol Biol. — PubMed PMID: 22231818 · doi:10.1007/978-1-61779-458-2_15

Mechanistic insights into nicotine withdrawal

Review, 2011. This review looks at how long-term nicotine exposure changes the brain, and how those changes produce withdrawal symptoms when a person stops smoking. It describes how nicotine takes over the brain's natural reward system, and how a small brain region called the habenula is part of a circuit behind the unpleasant effects of high nicotine doses and of withdrawal. It also summarizes what is known about the different nicotinic receptor types involved in withdrawal. The authors say this knowledge helps explain how current and future quit-smoking treatments work.

Paolini M, De Biasi M (2011). Mechanistic insights into nicotine withdrawal. Biochem Pharmacol. — PubMed PMID: 21782803 · doi:10.1016/j.bcp.2011.07.075

Reward, addiction, withdrawal to nicotine

Review, 2011. This review looks at how nicotine acts in the brain to drive reward, addiction and withdrawal. Nicotine works mainly through nicotinic receptors built from the alpha-4 and beta-2 subunits, often together with alpha-6, and it makes dopamine nerve cells in the midbrain fire faster and in bursts. With long-term exposure the brain adapts and comes to need nicotine to keep that altered state, so a withdrawal syndrome appears when nicotine is stopped. The authors report that the physical withdrawal symptoms depend mainly on a different set of nicotinic subunits (alpha-5, alpha-2, beta-4 and probably alpha-3) in a small brain region called the habenula and the areas it connects to.

De Biasi M, Dani JA (2011). Reward, addiction, withdrawal to nicotine. Annu Rev Neurosci. — PubMed PMID: 21438686 · doi:10.1146/annurev-neuro-061010-113734

Smoking, nicotine and neuropsychiatric disorders

Review, 2010. This systematic review of earlier research looks at why smoking is so much more common among people with psychiatric conditions. It covers how nicotine acts on the brain and its receptors, the role of the brain's reward system in nicotine addiction, and brain-imaging studies of dependence, craving and withdrawal. It also reviews population, brain-biology and genetic findings on smoking in several specific neuropsychiatric disorders, and why smoking matters for treating them. The authors describe tobacco smoking as an extremely addictive and harmful way of taking in nicotine, and say the brain biology behind the link between smoking and psychiatric illness is still unclear.

Dome P, Lazary J, Kalapos MP et al. (2010). Smoking, nicotine and neuropsychiatric disorders. Neurosci Biobehav Rev. — PubMed PMID: 19665479 · doi:10.1016/j.neubiorev.2009.07.013

Pharmacotherapy for tobacco dependence

Review, 2009. This review looks at the medicines approved to help people stop smoking. These are nicotine replacement products (a patch, gum, a lozenge, a tablet that dissolves under the tongue, an inhaler and a nasal spray), the antidepressant bupropion, and varenicline, a drug that partly activates the same nicotinic receptors in the brain that nicotine acts on. The authors explain how these medicines work in the body and which of their properties may affect how well they work, how safe they are and how likely they are to be misused. They also discuss how this knowledge could be used to improve current medicines and develop new ones.

Fant RV, Buchhalter AR, Buchman AC et al. (2009). Pharmacotherapy for tobacco dependence. Handb Exp Pharmacol. — PubMed PMID: 19184660 · doi:10.1007/978-3-540-69248-5_17

Sex differences in nicotine action

Review, 2009. This review looks at research on whether nicotine acts differently in males and females. It reports that women are less successful at quitting smoking, and that laboratory animal studies also show sex differences in how nicotine affects the brain, which suggests a biological basis and not only social factors. Differences in how the body processes nicotine, or the effects of sex hormones, may explain some but not all of these differences. The authors conclude that including sex as a factor in nicotine research could help make quit-smoking programs that work better for each person.

Pogun S, Yararbas G (2009). Sex differences in nicotine action. Handb Exp Pharmacol. — PubMed PMID: 19184653 · doi:10.1007/978-3-540-69248-5_10

Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics

Review, 2009. This review describes how nicotine acts in the body and how it keeps people addicted to tobacco. Nicotine attaches to nicotinic receptors in the brain and triggers the release of chemical messengers, especially dopamine, glutamate and GABA, which drive dependence; another brain signal, corticotropin-releasing factor, appears to contribute to withdrawal. The authors report that nicotine dependence is strongly inherited, and that people who break down nicotine at different speeds through the liver enzyme CYP2A6 differ in their risk of dependence, their response to quit-smoking treatment and their lung cancer risk. The review notes that tobacco addiction is much more common in people with mental illness or other substance use disorders, and lists nicotine replacement, bupropion and varenicline as treatments for tobacco addiction.

Benowitz NL (2009). Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol. — PubMed PMID: 18834313 · doi:10.1146/annurev.pharmtox.48.113006.094742

Tobacco addiction

Review, 2008. This review looks at tobacco addiction, which the authors link to 5 million deaths per year worldwide, and at how it is treated. It reports that drug and behavioural treatments help people quit, but many return to smoking, which the authors say shows how strongly addictive nicotine is. They say future treatment may come from better matching patients to treatments, combined or new drugs, and treating nicotine addiction as a long-term condition that may need long-term care.

Hatsukami DK, Stead LF, Gupta PC (2008). Tobacco addiction. Lancet. — PubMed PMID: 18555914 · doi:10.1016/S0140-6736(08)60871-5

Nicotine attenuates relapse to methamphetamine-seeking behavior (craving) in rats

Animal study, 2004. This study in rats looked at whether nicotine changes the urge to start taking methamphetamine again after the rats had stopped. The rats taught themselves to take methamphetamine for 10 days, then it was taken away, and on the sixth day without it a single methamphetamine dose made them start seeking the drug again. Giving the rats nicotine every day for 5 days while they were off methamphetamine reduced this drug-seeking, and a drug that blocks nicotinic receptors cancelled out the effect. The authors suggest that drugs which switch on nicotinic receptors might help prevent relapse to drug abuse, but this was shown only in rats.

Hiranita T, Anggadiredja K, Fujisaki C et al. (2004). Nicotine attenuates relapse to methamphetamine-seeking behavior (craving) in rats. Ann N Y Acad Sci. — PubMed PMID: 15542755 · doi:10.1196/annals.1316.062

Tobacco use and dependence

Review, 2003. This review article looks at tobacco use and dependence, including how nicotine acts in the body, how nicotine addiction develops, and the medicines used to treat it. It drew on professional journals, books and government publications. The authors conclude that smoking is addictive and a major health problem, and that regular nicotine use is central to keeping people dependent on smoking. They say nurses' knowledge of nicotine addiction is important in helping patients quit smoking.

Sohn M, Hartley C, Froelicher ES et al. (2003). Tobacco use and dependence. Semin Oncol Nurs. — PubMed PMID: 14702859 · doi:10.1053/j.soncn.2003.08.002

Managing nicotine addiction

Review, 2002. This review describes nicotine addiction, which it calls the main reason tobacco use continues so widely, and the medicines used to treat it. The authors report that several medicines roughly double long-term quit rates and are recommended as first-line treatment in US clinical practice guidelines: nicotine replacement therapy in the forms then available (gum, patch, nasal spray and inhaler) and the antidepressant bupropion. Two other drugs, nortriptyline and clonidine, also showed some benefit, and every medicine worked best when combined with behavioral therapy. The review also describes approaches still being studied, including new ways to deliver nicotine, a vaccine meant to stop nicotine from reaching the brain, and drugs that change how the body breaks nicotine down.

Kotlyar M, Hatsukami DK (2002). Managing nicotine addiction. J Dent Educ. — PubMed PMID: 12374267

The pharmacotherapy of smoking cessation

Review, 2002. This review looks at medicines that help people stop smoking. It explains that most smokers are dependent on tobacco, and that this dependence comes from the habits and sensations of smoking, reinforced within seconds by a fast burst of nicotine from the cigarette. The authors report that all forms of nicotine replacement therapy (gum, patches and inhaler) and the drug bupropion are safe and effective at raising quit rates in the short and long term, and that they work better when combined with counselling or behavioural support. They state that nicotine replacement is not recommended during pregnancy or for people with heart disease, but that if the alternative is smoking, it is almost certainly safe. They add that using more than one form of nicotine replacement may help people who failed on a single form and had withdrawal symptoms, and that bupropion has some specific reasons it should not be used.

Peters MJ, Morgan LC (2002). The pharmacotherapy of smoking cessation. Med J Aust. — PubMed PMID: 12065013 · doi:10.5694/j.1326-5377.2002.tb04521.x

Nicotine replacement therapy

Review, 1999. This review article explains how nicotine replacement medicines help people quit smoking. It describes the forms that were available at the time: gum, a skin patch, a nasal spray and a vapor inhaler. The authors explain that these medicines ease the body's withdrawal symptoms when a person stops smoking. Because they do not deliver the many toxins and cancer-causing chemicals found in cigarettes, the authors consider them safe when used as directed, and they also discuss the public health benefits of these medicines.

Fant RV, Owen LL, Henningfield JE (1999). Nicotine replacement therapy. Prim Care. — PubMed PMID: 10436291 · doi:10.1016/s0095-4543(05)70121-4

Nicotine replacement therapy

Review, 1998. This review looked at published research from 1982 to 1996 on nicotine dependence, how nicotine works in the body, its health effects, and nicotine replacement therapies used to help smokers quit. It reports that nicotine is what makes tobacco addictive: it stimulates nicotinic receptors, which encourages repeated use, and stopping it after long-term use causes withdrawal symptoms. Nicotine replacement therapy reduced the severity of withdrawal symptoms in people trying to stop smoking. The authors concluded that nicotine replacement chosen to fit the individual, combined with behavioral support, gave the highest success rates for quitting.

Thompson GH, Hunter DA (1998). Nicotine replacement therapy. Ann Pharmacother. — PubMed PMID: 9793600 · doi:10.1345/aph.17382

Treatment of nicotine dependence

Review, 1995. This review looks at drug and non-drug treatments for nicotine dependence, which the authors describe as the reason most smokers find it extremely hard to quit. Non-drug approaches, such as behavioral therapy, setting a quit date, counseling, self-help, hypnosis and acupuncture, ranged in effectiveness from substantial to almost nil. At the time, nicotine was the only drug approved by the FDA for quitting smoking, and nicotine replacement (a skin patch or chewing gum) used alongside non-drug support roughly doubled quit rates compared with placebo. The authors call the patch the first-line choice because it is easier to use than gum and works with minimal extra support, and they say clonidine, antidepressants and buspirone need more study.

Haxby DG (1995). Treatment of nicotine dependence. Am J Health Syst Pharm. — PubMed PMID: 7749954 · doi:10.1093/ajhp/52.3.265

The scientific case that nicotine is addictive

Review, 1995. This review looked at evidence from human and animal studies on whether nicotine is addictive. The authors report that smokers typically use nicotine compulsively and find the habit very hard to break. Studies in both animals and people showed that nicotine can act as a reward, though under a narrower range of conditions than some other drugs of abuse, and animals partly treat it like amphetamine and cocaine. They describe a clear nicotine withdrawal syndrome that nicotine replacement relieves, note that nicotine replacement roughly doubles quit-smoking success rates, and conclude that nicotine is a powerful addictive drug comparable to heroin, cocaine and alcohol.

Stolerman IP, Jarvis MJ (1995). The scientific case that nicotine is addictive. Psychopharmacology (Berl). — PubMed PMID: 7724697 · doi:10.1007/BF02245088

Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire

Review, 1989. This review looked at a widely used paper-and-pencil questionnaire that measures how dependent a smoker is on nicotine. Questionnaire scores matched other measures of nicotine dependence, including carbon monoxide, nicotine and cotinine levels in the body, but were only weakly linked to withdrawal symptoms. In quit-smoking trials without medication, the score predicted who would succeed. In trials using nicotine replacement, the link between score and success was less clear and may depend on the nicotine dose. The authors also describe problems with some of the questionnaire's items and with how the scale has been analysed.

Fagerstrom KO, Schneider NG (1989). Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J Behav Med. — PubMed PMID: 2668531 · doi:10.1007/BF00846549

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