7.16 Pharmacotherapies for smoking cessation

Last updated: August 2023

Suggested citation: Greenhalgh, EM., Dean, E., Stillman, S., & Ford, C. 7.16 Pharmacotherapies for smoking cessation. In Greenhalgh, EM, Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2023. Available from: http://www.tobaccoinaustralia.org.au/chapter-7-cessation/7-16-pharmacotherapy 


Note: This section is intended for health professionals. People who smoke tobacco and are interested in quitting can find information at: https://www.quit.org.au/ 

The development and introduction of pharmacotherapies has provided much-needed assistance for those people who smoke tobacco and are trying to quit, particularly for more dependent smokers. Pharmacotherapies for cessation primarily aim to reduce withdrawal symptoms and block the reinforcing effects of nicotine. A substantial body of research has demonstrated the effectiveness of such therapies for increasing smoking abstinence rates.In 2020, the US Surgeon General concluded that cessation medications are independently effective in increasing smoking cessation, and are more effective than self-help materials or no treatment.1 First-line treatments are those that have been shown to be effective and safe and are licensed for smoking cessation. These include nicotine replacement therapy (NRT), bupropion, and varenicline, all of which increase smoking cessation. Varenicline has generally been shown to be superior to bupropion and single forms of NRT, but equally effective as combination NRT (i.e., faster-acting plus longer-acting form). Table 7.16.1 shows the findings of recent Cochrane reviews examining the effectiveness of each first-line pharmacotherapy.

Table 7.16.1 Effectiveness of pharmacotherapies for smoking cessation


Relative effect (95% CI)

Nicotine replacement2


               Any form versus placebo/control

1.55 (1.49 to 1.61); i.e., users of NRT were 1.55 times more likely to successfully quit than placebo/control

               Nicotine gum versus placebo/control

1.49 (1.40 to 1.60)

               Nicotine patch versus placebo/control

1.64 (1.53 to 1.75)

               Oral tablets^/lozenges versus placebo/control

1.52 (1.32 to 1.74)

               Nicotine inhalator versus placebo/ control

1.90 (1.36 to 2.67)

              Nicotine nasal spray^ versus placebo/ control

2.02 (1.49 to 2.73)

               Mouth spray versus placebo/control

2.48 (1.24 to 4.94)



               Versus placebo/control

(1.52 to 1.77)

               Versus NRT (patch, lozenge, or a choice)

0.99 (0.91 to 1.09)

               Versus varenicline

0.71 (0.64 to 0.79)



               Versus placebo/control

2.24 (2.06 to 2.43)

               Versus NRT

1.25 (1.14 to 1.37)

               Versus bupropion

1.39 (1.25 to 1.54)

Combination therapies


               Combination NRT (faster-acting form + patch) versus single form5

1.25 (1.15 to 1.36)

               Combination NRT versus varenicline6

1.06 (0.75 to 1.48)

               Bupropion + NRT versus NRT alone3

1.19 (0.94 to 1.51)

                 Bupropion + varenicline versus varenicline alone3

1.21 (0.95 to 1.55)

Note: Italics indicate interventions for which there was no benefit over comparison group.
^ No longer available in Australia

Surveys in the US, UK, Canada, and Australia show that the self-reported use of any stop smoking medication has increased significantly over the 2000s. The most-used medication is NRT, with use of varenicline increasing significantly. Greater use of any medication is related to being female, white, and having a higher education level. 7,8

Choice of pharmacotherapy should take into account potential adverse effects as well as benefits.9 When pharmacotherapy combinations or dosages beyond those contained in product information and consumer medicines information are used, medical recommendation is necessary.

Cost is also taken into account by the Australian government in deciding which pharmaceuticals to subsidise under the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme (RPBS). Nicotine patches were listed on the RPBS in August 1994 and December 1995 and then made available under the PBS for Indigenous smokers from 2009. 10,11 Availability was extended to all smokers in January 2011. In April 2014, the 25 mg/16 hours patch was also added—see Section for further details on medicines listed. Bupropion and varenicline are Schedule 4 in Australia so that they are available only on prescription,12 and have been available on Australia’s PBS since 2001 and 2008 respectively. Since January 2023, the dispensed price for subsidised medicines is up to $7.30 for people with a concession card and up to $30.00 for other patients.13 Subsidy of medicines in Australia has clearly been associated with increased use.

Figure 7.16.1 shows the annual total number of prescriptions for each of the available anti-smoking medications and in total in Australia from 2001 to 2022. The sharp drop in varenicline prescriptions in 2021 reflects a pause in global distribution of Champix (see

Figure 7.16.1 Annual total number of prescriptions for anti-smoking medications, Australia, 2001 to 2022: bupropion, varenicline, and NRT

Source: Pharmaceutical Benefits Scheme database statistics http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp

Notes: Total number of prescriptions includes second and subsequent prescriptions for all classes of patients (general), those with concession cards and those covered by Repatriation Pharmaceutical Benefits Scheme) and some patients may have used more than one medicine over the 10-year period. NRT figures do not include over-the-counter sales of NRT.



This section summarises research on the use, effectiveness and safety of:

7.16.1 Nicotine replacement therapy

7.16.2 Bupropion and other anti-depressants

7.16.3 Varenicline and other nicotinic receptor partial agonists

7.16.4 Vaccines

7.16.5 Combination treatments (drug combinations, and drugs + behavioural support), and

7.16.6 Other medications that might increase quitting

It also examines:

7.16.7 The effects of dispensing arrangements and subsidies, and

7.16.8 Methodological and ethical issues in smoking cessation trials


7.16.1 Nicotine replacement therapy

Nicotine is the drug in tobacco that causes dependence.14 It is the decrease in nicotine levels that is mainly responsible for withdrawal symptoms after stopping smoking.14 NRT aims to temporarily replace some of the nicotine from cigarettes, in turn reducing motivation to smoke and nicotine withdrawal symptoms, and easing the transition from smoking to abstinence.9 By replacing only nicotine, the many thousands of other chemicals produced when tobacco is smoked that are largely responsible for tobacco-related disease are avoided. Hence NRT is sometimes thought of as ‘clean nicotine’.15

NRT products are either long-acting dosing forms or faster-acting forms.16 There are advantages and disadvantages associated with each form of NRT. Nicotine patches are simple to use and the adherence rate tends to be higher than other forms of NRT. 17,18 Patches deliver nicotine more slowly than other products and when used alone, may not adequately protect against increased cravings from smoking-related stimuli. Users of the faster-acting forms have greater control over the amount and timing of the dose, and these forms are better suited to respond to sudden increases in cravings.18 However, some people only use faster-acting NRT forms in response to cravings. Underdosing is a common problem, where people don’t use enough to obtain the best clinical effect.18 Nicotine delivered via a mouth spray  is absorbed faster than nicotine delivered via gum or lozenge. 19,20 There is robust evidence showing that combination NRT (long-acting plus faster-acting) is more effective than single‐form NRT5 (see Section, below).

E-cigarettes can provide users with inhaled doses of aerosolised nicotine. There is currently widespread debate within the public health community regarding the use and regulation of these products.21 From the 1 st of October 2021, consumers will require a doctor's prescription to legally access nicotine e-cigarettes and liquid nicotine in Australia—both domestically and when importing the products from overseas.22 See Chapter 18 for a detailed discussion. Mechanisms and pharmacokinetics of NRT

Several mechanisms have been proposed by which NRT may assist smoking cessation. First, NRT decreases the intensity of cravings and withdrawal symptoms, enabling people to function effectively while dealing with the social and psychological aspects of their dependence. NRT does not completely eliminate all withdrawal symptoms because the available delivery systems do not replicate the rapid and high levels of nicotine that result from smoking a cigarette.23 Second, it may reduce the reinforcing effects of tobacco-delivered nicotine. Third, it may provide some of the perceived effects for which the smoker previously relied on cigarettes, such as sustaining desirable mood, coping with stressful situations, and maintaining concentration. 18,24,25 The nicotine inhalator is designed to mimic the hand-to-mouth ritual of smoking. Efficacy and effectiveness of NRT

A Cochrane review published in 2018 concluded that NRTs increase the rate of quitting by 50 to 60%, and all of the commercially available forms can help increase the chances of a quit attempt being successful.2 However, some have suggested that this effect size may be an overestimate.26-28 Another review concluded that given the quality of research and the lack of serious adverse effects, NRT appears to be a safe and effective option for current smokers who wish to quit.29 A 2021 meta-analysis concluded that single-form NRT increases the odds of six-month abstinence by 2.2 times compared with placebo.30 Studies with long-term follow-up have found that the impact of a single course of NRT persists over time, with NRT users about twice as likely to not be smoking four years later than those who quit without using NRT.31 Dosage and mode of delivery

Some evidence suggests that dosage and speed of delivery has an impact on outcomes.32-35A review of high-dose transdermal NRT (patches) for smoking cessation published in 2014 concluded that there is insufficient evidence to support the safety and efficacy of this approach, and called for more robust trials.36 More recently, a 2019 Cochrane review found that people were more likely to quit successfully if they used higher‐dose compared with lower-dose nicotine patches or nicotine gum.5 Combination NRT therapy (longer-acting and faster-acting form)

In 2006, the Therapeutic Goods Administration (TGA) approved combination therapy for the concurrent use of the 15 mg 16-hour patch with 2 mg gum. There is robust evidence that combining a longer-acting form (e.g., patch) with a faster-acting form (e.g., lozenge) is more effective than single form NRT and is safe. 9,37-42A 2013 Cochrane review found that, comparable with varenicline, combination NRT (e.g., patch plus inhalator) was the most effective available pharmacological intervention for achieving smoking cessation,6 and a 2019 Cochrane review similarly concluded that using combination NRT versus single‐form NRT can increase the chances of successfully stopping smoking.5 In 2020, the US Surgeon General concluded that combination NRT increases smoking cessation compared with using single forms of NRT.1 A 2021 meta-analysis found that compared with placebo, people given combination NRT were 2.6 times more likely to successfully quit.30

Overall, researchers suggest that combination NRT likely represents the most promising smoking cessation strategy moving forward.43 Some have recommended that NRT labelling allow for combined use of faster-acting NRT forms with nicotine patch,37 and The Royal Australian College of General Practitioners has called for combination NRT to be subsidised under the PBS.44 The mechanisms underlying the effectiveness of combination NRT may include the higher percentage of nicotine substitution, more effective relief of cravings, and the sensory effects of different forms. 9,18 NRT combined with behavioural support

NRT works with or without behavioural support, however behavioural support further increases the odds of success.45-47 Although a combination of NRT and behavioural support is a well-established cessation method, one study found that self-reported abstinence rates were significantly higher among participants who were sent nicotine patches compared with a control group, supporting the effectiveness of NRT in isolation.48 Smokers making self-initiated quit attempts without formal behavioural support tend to have lower long-term success rates, but the relative effect of NRT is similar to the effects in other settings, offering significant improvement over unaided quitting. 9,49-51 Duration of use

An important factor affecting success rates appears to be the duration of NRT use. Pre-quit nicotine patch use appears to increase quit rates5 and may engage additional smokers who are unwilling to quit.37 The US Surgeon General’s report in 2020 found that pre-loading (e.g., initiating cessation medication in advance of a quit attempt), especially with the nicotine patch, may increase smoking cessation.1 The manufacturer’s recommended period of use for NRT forms substantially varies, often with provision for a gradual reduction of dosage levels to avoid withdrawal effects at the end of the period.52 However, research indicates that eight weeks of patch use is as effective as longer courses, and there is no evidence that tapered therapy is better than simply stopping after using the higher dose.9 Highly dependent smokers who still have cravings and withdrawal symptoms eight weeks after quitting may benefit from longer use. 18,53,54 Short courses of NRT, for example four weeks, may not be effective in the long term.55 Longitudinal research in Canada found that compared with  unassisted quitting, using NRT for less than 4 weeks was associated with a lower likelihood of quitting; however, using NRT for 4 weeks or longer was associated with a higher likelihood of cessation.56 After quitting, extended use of NRT may be beneficial for lapse recovery and relapse prevention in some smokers.37 Findings from a 2019 Cochrane review showed that while extended NRT use did not show a benefit in preventing relapse in assisted abstainers, extended use in unassisted abstainers did suggest a benefit. However, the evidence was of low certainty.57 Continued use of NRT and tobacco during a lapse or relapse does not appear harmful and could enhance quitting outcomes.58 For example, one study found that if people continue to use a nicotine patch ( after a lapse they are 4–5 times more likely to quit.59 The Royal Australian College of General Practitioners has recommended that a second 12-week round of NRT be subsidised under the Pharmaceutical Benefits Scheme within a 12-month period, to allow for extended use to prevent relapse.44 Factors affecting use and adherence

The widespread availability and promotion of NRT forms has led to increased use, however there are concerns that use of the products in the community appears to be more haphazard and less effective than among participants in research trials. A meta-analysis found poor adherence to NRT among participants of population-based studies, with only about one in four people taking it as directed.60 A population-based study in England found that smokers attempting to reduce their cigarette intake are often underusing NRT, which may explain why real-world studies often report less success with NRT than clinical trials.61 A study in New South Wales found that more than 40% of people who had used NRT in their most recent quit attempt had no instruction from a doctor or pharmacist on how to use the product, 61% used it for less than two weeks, and for about one-third of people, use was concurrent with smoking.17

Research suggests that many smokers have misperceptions about the health risks of NRT, which makes them less likely to use the NRT or use it correctly. 34,47,62 Smokers tend to use less than the recommended dose or not complete the full course of treatment. 63,64 Treatment adherence has been found to significantly increase abstinence rates. 60,65 Using more doses of nicotine gum, nicotine lozenges and nicotine inhalator, increases quit rates. 66,67 For example, one study found that for each additional lozenge used, the odds of successful quitting increase by 10%.68 Approaches to increase smokers’ willingness to use—and correct use of—NRT include addressing their expectations of its effectiveness, explaining clearly how it works, tailoring treatment plans, and addressing barriers to use.69 Clear and accurate information regarding the safety of NRT from health professionals can increase use and adherence.70 The literacy levels of packaging and instructions have been assessed as being above the reading levels recommended to ensure maximum comprehension.71 There is some evidence that enabling smokers to sample the NRT forms prior to use may result in more realistic choice of NRT and better compliance.72

The use of NRT for a reason other than quitting, including temporary abstinence or reducing consumption, appears to be common. A review of NRT products available in Canada found that while more robust studies are needed to test newer products (such as a nicotine mouth spray or mini lozenges), NRT appeared to be effective in smoking reduction for those smokers who did not want to quit, failed from previous NRT, or intended to quit smoking gradually.73 Such usage is associated with higher education level, heavier smoking, no intention to quit, no quit attempts in the past year and the type and availability of the product used. These patterns of use may help to explain why significant benefits of NRT use are not easily detected in population studies.74 Safety of NRT

In general, NRT is considered to be safe for most users. Discontinuation because of adverse reactions is relatively low.9 Using NRT to quit is always safer than continuing to smoke.75 When used as directed, users of NRT typically absorb a lower daily dose of nicotine than they would get from smoking a pack of cigarettes per day. 18,76 While there has been concern about the potential for symptoms of nicotine overdose, studies of higher dose products and combination of NRT products have found no evidence of harm from moderate increases in nicotine intake. 75,77,78 Further, research suggests that using faster-acting NRT forms  alongside smoking does not appear to increase average nicotine levels, although smoking while using the nicotine patch does.77 Smoking while using NRT does not significantly increase the risk of a heart attack or other cardiovascular events. 9,75 No serious adverse effects have been reported in studies of concomitant smoking and NRT use, although one study reported that nausea and vomiting were more common in the active than the placebo group. 18,77 Other potential symptoms of nicotine overdose include pallor, sweating, tachycardia, agitation, and a number of less common symptoms.52

All NRT products have a low addictive potential.79 Addictive potential is strongly influenced by speed and method of delivery of nicotine. 75,80 When smoking a cigarette, peak blood nicotine levels are achieved within seconds, taking only 10–19 seconds for nicotine absorbed from the lungs to reach the brain, after which time it declines rapidly.75 In contrast, it can take more than 30 minutes to reach the peak blood nicotine level when using faster-acting forms of NRT,81-84 with effects of nicotine evident within 15–20 minutes.18 When using the patch, it takes four to nine hours (depending on the patch) to reach peak blood nicotine level, which then remains constant while wearing the patch.76

A paper examining the first 20 years of NRT use reported no serious adverse effects of either short or long-term use.54 The most common side effects of the patch are skin rashes where it is applied and sleep disturbance. Common side effects for the faster-acting forms include irritation of the mouth or throat, headaches, hiccups, indigestion, nausea and coughing. 9,52,76,85,86 These are relatively minor for most users, and NRT is generally rated as safe compared to other medications. 9,54 Although such use is uncommon, extended duration NRT is safe, and is at least as effective as short courses. 37,87

While NRT has the potential for adverse effects in vulnerable developmental stages (such as during adolescence, pregnancy, and breastfeeding), it is considered to be safer alternative to smoking and can be considered under medical supervision. 88,89 NRT is safe to use  in people with stable cardiovascular disease, including angina and previous heart attack. 9,75 Nicotine does have some effects on the cardiovascular system, such as increased heart rate and blood pressure, however it is not the major cause of increased cardiac risk due to smoking.75

Many smokers believe that nicotine causes cancer, since it is equated with tobacco; 75,90 however, the US Surgeon General’s 2014 report concluded that there is insufficient data to conclude that nicotine causes or contributes to cancer.91 It appears to be the other carcinogens in tobacco smoke that are responsible for smoking-related cancers. 92,93 Using NRT to ‘cut down to quit’

Many smokers find it very difficult to stop using tobacco abruptly even using NRT. In 2007, the TGA approved the use of the ‘cut down and stop method’, where smokers using NRT (inhalator, mouth spray, lozenge or gum) reduce the amount they smoke over a six-week period before stopping completely. Research suggests that the addition of this method to the approved uses of NRT may increase the numbers of smokers who quit altogether.94 Pre-quit nicotine patch use appears to increase quit rates and may engage additional smokers compared with starting the patch on quit day. 37,77,95,96

There has been discussion about offering NRT to smokers not wanting to quit but who are interested in reducing their level of smoking. The rationale is that once reduced, they may decide to quit altogether. Studies of smokers cutting down while using NRT have found that while blood nicotine levels generally remain stable or slightly higher, carbon monoxide readings decreased.97-99 Research is limited but trials indicate that NRT can achieve sustained smoking abstinence in this group. However, most trials also provided some type of behavioural support. 100,101 Evidence suggests that use of NRT to ‘cut down to quit’ is effective and cost effective compared to no quit attempt.102 Scheduling and subsidy of NRT

In Australia, NRT is available in the form of a patch, gum, lozenge, mini-lozenge, mouth spray, and inhalator. The gum and lozenge come in 4 mg and 2 mg strengths, while the inhalator comes in a 15mg strength. The mini lozenges come in strengths of 4mg and 1.5mg. A mouth spray delivers 1 mg per spray, while the dose from an inhaler is similar to that of the 2 mg gum. There are two types of patches, each with three strengths: the 24-hour patch 21 mg, 14 mg and 7 mg strengths, and the 16-hour patch 25mg, 15 mg, and 10 mg strengths.103 Nicotine chewing gum first became available on prescription in Australia in 1984, followed by the patch in 1993.104 The 2 mg gum became available over-the-counter without prescription (i.e., became unscheduled) in pharmacies in 1988, and the 4 mg gum and patches in late 1997.105 The nicotine inhaler, lozenges and sublingual tablets were introduced as over-the-counter products in 1999, 2002 and 2003 respectively. 82,83,85 In 2005, NRT products started to appear in supermarkets. Direct advertising to the public of NRT began in 1998, which markedly increased sales.

Subsidised nicotine patches have also been available since 1994 to patients eligible for repatriation benefits and to patients who identify as Aboriginal or Torres Strait Islander since January 2009. Access to nicotine patches under the PBS was extended to all smokers in February 2011, and lozenges and gum were also added to the PBS in 2018. A condition for the subsidy is that the smoker participates in cessation counselling.

As of August 2023, there were 7 nicotine replacement patch products  available on the PBS and/or RPBS. Nicotine gum and lozenge formulations were removed from the PBS on 1 July 2023.106 For further details about  individual products, see here. Since June 2023, all patients can now receive 2 x 12-week PBS-subsidised treatment courses per 12-month period.107  If a patient is unsuccessful in quitting using NRT, they can access other smoking cessation therapies on the PBS (bupropion and varenicline) during that 12-month period.


7.16.2 Bupropion and other anti-depressants

Bupropion is a non-nicotine medication that is approved for use as an aid to smoking cessation. Originally developed as an antidepressant, early users reported that they had less urge to smoke, and further research demonstrated that it was useful as an aid to quitting. Mechanisms and pharmacokinetics of bupropion

The active ingredient is bupropion hydrochloride. The tablets are ‘sustained release’ which mean the buproprion is released slowly and absorbed,108 While the exact mechanism by which bupropion supports smoking cessation is unknown, its action is likely mediated through the noradrenergic and/or dopaminergic pathways.109 It relieves withdrawal symptoms and may reduce depressed mood, 108,110-112 and symptoms of depression.113 Use of bupropion is associated with improved ability to resist cravings that result from ‘cues’ to smoke.114 Bupropion appears to reduce the weight gain that occurs after quitting, but the effect does not last beyond treatment.108 Efficacy of bupropion

A Cochrane review published in 2020 concluded that there is high quality evidence that bupropion increases the likelihood of long-term smoking cessation. People who use bupropion are about 60% more likely to achieve long-term cessation (vs. placebo/control), which is similar to that for single-form NRT, but lower than when using varenicline.3 A 2021 meta-analysis concluded that bupropion increased the odds of six-month abstinence by 2.1 times compared with placebo.30 The Cochrane review did not find any evidence that the efficacy of bupropion depended on the level or type of additional behavioural support, or whether people had a psychiatric condition.3  There is some evidence that positive beliefs and attitudes about bupropion are associated with being positive about quitting, better compliance, and potentially better outcome.115 One study found that extended use of bupropion prior to a quit attempt reduced smoking behaviour during the pre-quit period and improved short-term abstinence rates.116 A 2019 Cochrane review concluded that extended treatment with bupropion did not appear to help prevent relapse; however uncertainty in the data meant that the authors could not rule out such a benefit.57 People with certain genetic variants appear to have lower success rate with bupropion, highlighting the potential for genetic markers to guide individualised pharmacotherapy.117 Use of bupropion in Australia

Bupropion was introduced into Australia in 2000 and listed on the PBS in February 2001, sold as 30 x 150 mg tablets (code 8465M), since February 2001 and 90 x 150 mg tablets (code 8710K), since February 2004.

It is available only on prescription, and one nine-week course per year is subsidised under the PBS on condition that users participate in a comprehensive counselling program such as with the Quitline. Since changes to the authority conditions in 2004, smokers wishing to use bupropion must visit a doctor for the initial 30-tablet prescription, and then make a second visit to receive the second prescription for the remaining 90 tablets. Adverse events associated with bupropion

The most common side effects of bupropion use are sleeping difficulties, dry mouth, headache, dizziness, anxiety and nausea. 113,118 A small number of allergic reactions to bupropion have been reported, including skin rashes or breathlessness, and, less frequently, fever, muscle and joint pain. 108,118 Overdosing can cause serious side effects, including vomiting in children, rapid heartbeat in teenagers and adults and seizures. Other effects of overdose include lethargy, confusion and tremors.108 The most serious side effect is a risk of seizure, estimated to occur in 1 in 1000 patients.113 One review found that cardiovascular events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion compared with placebo.119 While a large randomised trial found that use of bupropion did not appear to increase the risk of neuropsychiatric adverse events,120 a 2020 Cochrane review found high‐certainty evidence that participants randomised to bupropion were more likely to report psychiatric adverse events. This along with other side effects resulted in more trial dropouts. However, there was insufficient evidence regarding whether participants taking bupropion were more likely than those taking placebo to report serious adverse events, such death or hospitalisation.3 Bupropion is contraindicated for smokers who are allergic to bupropion, who are pregnant or breastfeeding, who are less than 18 years of age, who have a current or previous history of seizures or eating disorders, who are currently or recently (within last 14 days) taking monoamine oxidase inhibitors, who have any tumours of the central nervous system or severe liver disease, or who are undergoing abrupt withdrawal from alcohol or benzodiazepines. 121,122 There is also an increased risk of seizures occurring with bupropion in the presence of predisposing risk factors which lower the seizure threshold.109 Other antidepressants

A number of other antidepressants have been investigated for smoking cessation.A 2020 Cochrane review3 and a 2021 meta-analysis30 both concluded that the antidepressant nortriptyline approximately doubles the odds of six-month abstinence compared with placebo. The side effects of this medication include dry mouth, constipation, nausea, and sedation, and it can be dangerous in overdose. Like bupropion, the likelihood of quitting using nortriptyline appears to be similar to that for NRT, but lower than when using varenicline. Selective serotonin reuptake inhibitor antidepressants (for example, fluoxetine), monoamine oxidase inhibitors (for example, selegiline), and the antidepressant venlaxafine have not been shown to help smoking cessation, nor has the herbal therapy St John's wort, or S-Adenosyl-L-Methionine (SAMe), a dietary supplement that is thought to have antidepressant properties. 3,113

None of these drugs are currently licensed for smoking cessation in Australia; however, nortriptyline is licensed for smoking cessation in New Zealand3 and is sometimes prescribed ‘off-label’ in Australia for people trying to quit.123  

7.16.3 Varenicline and other nicotinic receptor partial agonists

Varenicline is derived from cystine, a similar drug that has been used to assist cessation in central and eastern European countries for several decades. The active ingredient is varenicline tartrate.124 An extensive body of evidence supports the use of varenicline as a smoking cessation medication in a broad range of tobacco users with medical, behavioural, and diverse demographic characteristics.125 Mechanisms and pharmacokinetics of varenicline

Varenicline is a nicotinic receptor partial agonist (i.e., it binds to nicotinic acetylcholine receptors), which maintains moderate levels of dopamine to reduce withdrawal symptoms and the urge to smoke. It also acts as an antagonist by blocking nicotine binding to specific receptors, which may reduce the rewarding effects of smoking and reduce reactivity to smoking cues. 4,124,126-128 Recent research also suggests that varenicline's reduction of reward anticipation in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, can independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation.129 Some evidence suggests that varenicline improves cognitive performance among highly dependent smokers using the medication to quit.130 Efficacy of varenicline

A robust body of evidence supports the efficacy of varenicline as a smoking cessation medication. A 2016 Cochrane review concluded that varenicline increased the chances of successful long-term cessation between two- and three-times compared to attempts with no medication. It may also help to prevent relapse.4 A 2021 meta-analysis concluded that nicotine receptor agonists increased the odds of six-month abstinence by 2.7 times compared with placebo.30 A ‘real-world’ study found that the continuous abstinence rate of varenicline users was 44.4%, with no significant gender or age differences. For every day that varenicline was taken, abstinence increased by an average of 6.6 days.131 For smokers ‘cutting down to quit’, a randomised clinical trial found that use of varenicline significantly increased smoking cessation rates at the end of treatment (6 months), and also at 1 year.132

 A number of international studies have shown that varenicline is well tolerated and can be regarded as a cost-effective cessation treatment in smokers willing to quit, including users of smokeless tobacco.133-146   It also appears to be equally effective for light and heavy smokers.147 Varenicline has been found to be effective and safe  in those with stable mental illness or a past history of mental illness.148 There is also evidence that varenicline is effective and safe for smoking cessation in people with schizophrenia. 149,150

Varenicline has generally been shown to be superior to bupropion and NRT. 110,120,141,151-156 For example, one ‘real world’ study found that varenicline users were 3.83 more likely to be abstinent than users of NRT following a quit attempt,157 and several Cochrane reviews have also concluded that varenicline is more effective than bupropion or NRT. 3,4   A double-blind randomised trial found that varenicline, compared with nicotine patch, more than doubled the odds of end-of-treatment abstinence among a sample of women smokers, although this diminished somewhat at post-treatment follow-up.158 On the other hand, a randomised clinical trial published in 2016 that compared the efficacies of 12 weeks of treatment with varenicline, combination NRT (patch + lozenge), or the nicotine patch alone found no significant differences in rates of abstinence at 26 weeks, indicating that all three treatments were equally effective.159 One meta-analysis similarly concluded that combination NRT and varenicline are equally effective for quitting.6  

Extended use of varenicline may also be effective.160-162 Limited data indicates that smokers using varenicline who have an initial delay in quitting have increased risk of relapse and may benefit from extended use of the medication.163 A 2019 Cochrane review similarly found that extended treatment with varenicline can help to prevent relapse.57 Initiating varenicline use several weeks prior to quitting, known as preloading, may also increase cessation rates.164 A study examining the efficacy and safety of retreatment with varenicline concluded that the medication is efficacious and well tolerated in smokers who have previously taken it. Abstinence rates were comparable to those reported for varenicline-naive smokers.165 Lower doses are also beneficial while lessening the incidence of adverse events.4 One study found that increasing varenicline dose in smokers with low response to the drug had no significant effect on nicotine withdrawal symptoms or smoking cessation.166 Although some studies have shown compliance to be an issue,167 varenicline appears to be effective in increasing cessation at 12 months even when compliance with the medication is not 100%.168 Certain genotypes also appear to be associated with higher odds ratio for success in individuals on varenicline therapy.169 Use of varenicline in Australia

Varenicline was introduced into Australia as Champix® on 1 January 2008, as a prescription medicine available on the PBS to smokers enrolled in a smoking cessation counselling program.170 It was available in three different configurations:

  • 56 x 1 mg tablets (1 pack/12 week course: code 5469W, 2 packs/24 week course: code 9129L)
  • 11 x 0.5 mg tablets and 14 x 1 mg tablets in the first pack and 42 x 1 mg tablets in the second pack (code 9128K)

In 2021, a shortage of Champix was announced due to a pause in global distribution of by the manufacturer (Pfizer), while a potential issue of contamination is investigated. The shortage is projected to impact supplies into 2024.171 As of August 2023, the TGA has approved two alternative brands due to this shortage; Varenapix (1mg and 0.5mg/1mg composite) have been registered on the Australian Register of Therapeutic Goods (ARTG)172 , 173 and S19A APO-varenicline (1mg and 0.5mg) have been approved for import and supply but are not registered on the ARTG174 , 175 . As of August 2023, Varenapix (1mg) and S19A APO varenicline (1mg and 0.5mg) are available on the PBS to smokers enrolled in a smoking cessation counselling program.170

Varenicline is not suitable for pregnant women, children under 18 years of age, or people allergic to varenicline tartrate. 124,176 The manufacturers’ list of illnesses for which medical advice may be needed includes having a mental illness or a history of mental illness,  renal impairment, and history of seizures or other conditions potentially lowering the seizure threshold.177 Caution is recommended when operating vehicles or heavy machinery.178

Data from a number of countries show that since being introduced, varenicline has become the second most used cessation medication, behind NRT, including in Australia. Between 2006 and 2008 varenicline use rates increased from 0.0 to 14.5%. The findings suggest that varenicline did not simply gain market share at the expense of other medications, but led to an increase in smokers using evidence-based treatment.7 In the US, the introduction of varenicline coincided with a net increase in attempts to quit smoking and, among these, a net increase in use of stop-smoking medications.179 Canadian research concluded that both standard and extended courses of varenicline are cost-effective treatment regimens compared with alternative smoking cessation interventions.180 Adverse events associated with varenicline

Varenicline is well tolerated by most people who use it. 124,178,181 The main side effect of varenicline is mild to moderate nausea, affecting about 3 out of 10 people. 4,124  There is some evidence that nausea can be minimised by taking with food, titration and self-regulation of varenicline (0.5-2mg/day).182  Other side effects include stomach or bowel problems (e.g. constipation, gas, dry mouth, vomiting, indigestion), headache, dizziness, sleeping problems, unusual dreams, feeling tired, increased appetite and changes in taste.124 These side effects are usually mild to moderate and decrease over time. 4,124,156,181Side effects usually occur in the first week of taking the medicine.124 There is some evidence of adverse gastrointestinal effects when varenicline is used at maintenance dose.183 In the US, the FDA have noted a number of adverse reactions in patients drinking alcohol while being treated with varenicline, including increased intoxication, loss of memory, and aggressive or uncharacteristic behaviour. It recommends reducing alcohol consumption until the patient knows to what extent the medication affects their capacity to tolerate alcohol.184

Varenicline may cause other, less common side effects.124 Serious side effects are rare and estimated to affect up to 1 in 1000 people (0.1%).156 Very serious side effects that require urgent medical attention or hospitalisation may affect up to 1 in 10,000 people (0.01%).124 Safety warnings and revised labels have been issued in response to serious side effects from overdosing.124 Although there have been ongoing concerns about a possible association between varenicline and heart attack or stroke, a retrospective cohort study in England found that neither bupropion nor varenicline showed an increased risk of any cardiovascular event compared with NRT.185 A meta-analysis also found no increase in the risk of all cardiovascular disease events with bupropion or varenicline.186 A review paper concluded that there is sufficient evidence to suggest that benefits of using cessation pharmacotherapies outweighs the low risk of serious adverse cardiovascular events associated with their use, particularly in light of the high cardiovascular risk from continued smoking.187

Some people report experiencing psychiatric symptoms when they start taking the varenicline, such as depression, agitation, aggression, thoughts of self-harm, self-harm, thinking about suicide, suicidal behaviour, and hallucinations. 4,124 However, a 2016 Cochrane review concluded that recent observational cohort studies and meta-analyses have not confirmed fears of a causal link between varenicline and psychiatric symptoms, including depressed mood, agitation, and suicidal behaviour. However, the evidence was not conclusive in people with past or current psychiatric disorders.4 Another 2016 systematic review and meta-analysis, this time of varenicline for smoking cessation and reduction in people with severe mental illnesses, concluded that varenicline appears to be significantly more effective than placebo for helping people with severe mental illness to reduce or quit smoking, with no clear evidence of increased risks or adverse events.188 Results of a large-scale randomised controlled trial similarly found that there was not a significant increase in neuropsychiatric adverse events attributable to varenicline.120 A large cohort study in the US found no increased risk of cardiovascular or neuropsychiatric hospitalisations in varenicline users compared with those who used NRT,189 while a British study found that varenicline was associated with a decreased risk of death, serious cardiovascular events, and neuropsychiatric events compared with NRT.190 Other nicotinic receptor partial agonists

Cytisine is a nicotinic acetylcholine receptor partial agonist.191 A systematic review and meta-analysis published in 2013 concluded that cytisine is an effective treatment for smoking cessation with efficacy comparable to that of other currently licensed treatments,192 and another more recent review similarly concluded that cytisine is a low-cost medication that can increase the likelihood of smoking cessation.193 The US Surgeon General concluded in 2020 that cytisine may increase smoking cessation.1 In comparing the effectiveness of cytisine with NRT for smoking cessation, New Zealand researchers found that when combined with brief behavioural support, cytisine was superior to NRT in helping smokers quit. Although it was associated with a higher frequency of self-reported adverse events, only 5% of people stopped taking it because of them. It is also low-cost compared with many other pharmacotherapies, potentially making it more accessible to low income people and countries.194 One evaluation estimated that cytisine is both more clinically effective and cost-effective than varenicline.195

7.16.4 Vaccines

In recent years, researchers have been attempting to develop vaccines that create antibodies that bind to nicotine in the bloodstream and prevent it from entering the brain, thus reducing the rewards of smoking and promoting cessation. 16,196 197,198 Despite promising preclinical trials,199 clinical trials have not supported the efficacy of the products,200-202 and none are yet approved cessation aids. Nonetheless, researchers have suggested that there is good reason for continued optimism,202 and that next-generation immunotherapies are likely to be substantially more effective than first-generation vaccines.203  For example, some studies have found that subjects with high anti-nicotine antibody levels demonstrate higher quit rates after receiving nicotine vaccines.204-208Therefore, vaccines that consistently generate higher antibody levels could be effective therapies.203 Another study has identified which of two types of nicotine is the best to target when developing nicotine vaccines.209

7.16.5 Combination treatments Drug combinations

Combining approved medications is one approach to potentially improving cessation outcomes. There is robust evidence that combining a longer-acting form of NRT (e.g., patch) with a faster-acting form (e.g., lozenge) is more effective than single-form NRT and is safe9 —see Section  

Drugs with different mechanisms and pharmacokinetics may also be combined. Most of these combinations are yet to be approved but some show promise.65A systematic review and meta-analysis found that combination therapy of varenicline with NRT patch is better than varenicline alone.210 A systematic review published in 2016 concluded that combination bupropion and varenicline appears to have greater efficacy in smoking cessation than varenicline alone.211 A meta-analysis published in 2021 found that the most effective combination of cessation medications for achieving six-month abstinence was a nicotinic receptor agonist with NRT. Compared with placebo, smokers given this combination were 4.4 times more likely to successfully quit. Those given bupropion with a nicotinic receptor agonist were four times more likely to quit for six months, and bupropion and NRT 3.8 times more likely, compared with placebo.30 Drug plus non-drug therapies

A ‘real-world’ population study in England found that smokers who use a combination of behavioural support and pharmacotherapy in their quit attempts have almost three times the odds of success than those who use neither pharmacotherapy nor behavioural support.212 In a systematic review published in 2015, the US Preventive Services Task Force found that combined behavioural and pharmacotherapy interventions increased cessation by 82% compared with minimal intervention or usual care.213 A 2016 Cochrane review concluded that combining pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. The authors did not find evidence that offering more intensive behavioural support was associated with larger treatment effects.214 Another Cochrane review published in 2019 concluded that providing behavioural support in person or via telephone for people using pharmacotherapy to stop smoking increases quit rates. Increasing the amount of behavioural support is likely to increase the chance of success by about 10% to 20%.215 The US Surgeon General concluded in 2020 that while behavioural counselling and cessation medications are independently effective in increasing smoking cessation, they are even more effective when used in combination.1 A review of combination therapies found that varenicline combined with behavioural therapy appears to be more effective than other pharmacotherapies combined with behavioural therapy.42

7.16.6 Other medications that might increase quitting

Many pharmaceutical companies and research institutions are investigating the potential for developing smoking cessation products that interfere with mechanisms involved in nicotine addiction. 16,23,65,198,216Drugs that target the cannabinoid receptor system have also been investigated.217 Rimonabant is used predominantly for treating obesity, but some thought it would also be useful for smoking cessation, particularly for smokers concerned about weight gain. 18,218 Early clinical trials suggested a benefit for long-term smoking cessation and reduction of weight gain, especially in overweight or obese individuals.219 However, increased psychiatric side effects appeared in clinical trials.16 In October 2008 the manufacturer discontinued development of the drug.198

A pilot study based on evidence that glutamate transmission plays an important role in relapse examined a cysteine pro-drug, N-acetylcysteine (NAC) and concluded the results were encouraging.220 However, a subsequent systematic review did not support its use for aiding cessation.221 Methoxsalen  blocks the enzyme that breaks down nicotine in the body, slowing elimination, thus potentially postponing the onset of withdrawal symptoms and making cessation easier.222 Initial research in mice suggests that combining the drug with NRT may have a beneficial role in treating nicotine dependence. 223,224

Topiramate is an anticonvulsant medication that may be effective as a treatment for alcohol and cocaine addiction, which has been proposed as a potential cessation aid.225-228A pilot randomised controlled trial in 2014 found that topiramate, alone or in combination with NRT, resulted in a higher quit rate than placebo and decreased weight.229 However, a meta-analysis published in 2020 investigating the effectiveness of topiramate in smoking cessation found insufficient evidence for its use.230

Although naltrexone has been used to successfully treat opioid and alcohol dependence, 231,232 a 2013 Cochrane review concluded that there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, and a 2014 systematic review and meta-analysis arrived at similar conclusions. 233,234 An Australian drug company has reported findings from a clinical trial showing that smokers administered the respiratory drug INV102 (nadolol) were more likely to stop smoking completely, or dramatically reduce the number of cigarettes smoked. The drug may also be useful for treating epithelial damage (i.e., damage to the tissues that line the blood vessels and organs) caused by smoking.235 A 2004 Cochrane review found low-quality evidence that the blood pressure medication clonidine may increase smoking cessation.236Side effects include postural hypotension, extreme drowsiness, fatigue and dry mouth, which limit its usefulness.182

Silver acetate was marketed in the 1970s and 1980s as smoking deterrents or aversion therapy, because it produced an unpleasant taste when smoking. A 2012 Cochrane review concluded that existing trials show little evidence for a specific effect of silver acetate in promoting smoking cessation, and any effect of this agent is likely to be smaller than NRT.237

New research focusing on pharmacogenetics is emerging, based on the discovery of genetic properties influencing the pharmacokinetics and pharmacodynamics of nicotine.65 Genetic-based methods may be useful in predicting response to pharmacotherapy for sub-groups of smokers and assist the personalisation of treatments. 55,238-242See Section for a detailed discussion.

7.16.7 Effects of dispensing arrangements and subsidies

Research in the Netherlands found that a national reimbursement policy for smoking cessation treatment that is accompanied by media attention can increase cessation.243 Canadian research also found that the adoption of a smoking cessation medication coverage drug policy was an effective intervention to improve quit rates, the advantages of which were lost once coverage was discontinued.244 A Cochrane review similarly concluded that the provision of financial assistance for smokers trying to quit increase the proportion of smokers who attempt to quit, use smoking cessation treatments, and succeed in quitting.245

Since February 2011, Australian smokers have been able to access a 12-week supply of nicotine patches under the PBS as long as they have a medical prescription.246 Data from the Australian National Drug Strategy Household Survey show that among adult regular smokers, past year use of NRT (gum, patches, or inhalers) increased significantly from 14.9% in 2010 to 16.7% in 2013 (controlling for age and sex), after this change was implemented.247 Similarly, Australian research has found that reported use of prescription medication to quit smoking rose sharply with the addition of varenicline to the PBS.248

In the US, Quitlines often provide free NRT to callers. Evaluations have found that such programs increased the number of callers, in some cases quite dramatically, and most found that access to free NRT improved long-term quit rates.249-260 One US study also reported that the majority of recipients of their program were from disadvantaged groups.261 One study in which GPs gave a personalised letter to patients who smoke that encouraged them to quit and offered free NRT increased the number of smokers making a supported quit attempt.262 Another found that providing free NRT samples engaged both motivated and unmotivated smokers into the quitting process and produced positive changes in smoking outcomes.263

7.16.8 Methodological and ethical issues in smoking cessation trials

 Clinical research is increasingly being sponsored by companies that make the products under investigation, either because the companies directly perform the studies, or fund them.264 Potential ways that industry sponsors can influence the outcome of a study include the framing of the question, the design of the study, the conduct of the study, how data are analysed, selective reporting of favourable results, and ‘spin’ in reporting conclusions.264 A meta-analysis published in 2007 concluded that NRT trials with pharmaceutical industry funding tend to show higher success rates than those independently funded.265 The authors suggest that one possible reason for this difference may be greater resources in industry-sponsored trials, leading to higher treatment compliance and therefore greater efficacy.265 A follow-up study in 2010 found that the differential efficacy of NRT between industry-sponsored and non-industry trials may be caused by differences in the quit rate among those in the placebo condition, perhaps due to characteristics of participants recruited (in particular heaviness of smoking or level of tobacco dependence), the exclusion of participants with confounding comorbidity (such as psychiatric disorder) or the number of study sites.266 A 2012 Cochrane review concluded that sponsorship of drug and device studies by the manufacturing company leads to more favourable results and conclusions than sponsorship by other sources.264 Such trials may receive more scientific attention than trials with unfavourable findings, resulting in an overestimation of effectiveness.65  

Although there is robust evidence from clinical trials for the effectiveness of pharmacotherapies and behavioural interventions for quitting, population-based or ‘real-world’ studies have produced mixed results, with some reporting less successful quit rates. Randomised controlled trials that enrol highly motivated smokers who are carefully followed up and who receive higher intensity behavioural support than is usually provided may report higher cessation rates than would occur in general population use of the medications.65 Several papers have raised concerns that strict selection criteria in cessation trials mean that many smokers are excluded from such trials, and therefore the findings may not be valid or generalisable. 267,268 Further, more dependent smokers may be more likely to use some form of treatment, but with less success, and this may artificially lower success rates.94 Researchers have argued that real-world studies of cessation treatments have often failed to adequately control for the fact that smokers who use these medications are more dependent upon cigarettes. Nonetheless, after adjusting for major confounding variables such as tobacco dependence, findings from population studies in England support the efficacy of combined behavioural therapy and pharmacotherapy for tobacco dependence treatment, thus supporting their use in the real world. 212,269

A recent review has also highlighted that using a consistent definition of abstinence in smoking cessation clinical trials is crucial to both comparing results across clinical trials and for including the data in meta-analyses. It concludes that defining abstinence requires specification of which products a user must abstain from (i.e., combustible tobacco, smokeless tobacco, and/or alternative products such as e-cigarettes), the type of abstinence (i.e., point prevalence or continuous), and the duration of abstinence (end of treatment, ≥3 months after the end of treatment, and ≥6 months post-quit or post-treatment initiation).270 Another review notes that biochemical verification of tobacco use and abstinence increases scientific rigour and validity compared to self-reported cessation, but should be considered in light of its costs and limitations, including the cost of the assays, the feasibility of sample collection, the ability to draw clear conclusions based on the duration of abstinence, and the variability of the assay within the study population.271

Another important methodological consideration in cessation studies is the extent to which smokers’ compliance with directions for using and taking smoking cessation medications affects outcomes.65 There is evidence that the majority of smokers using stop-smoking medications do not complete the recommended course of treatment. 60,63 Reasons for premature discontinuation of medication include relapse back to smoking, reported side effects and the perception that the medication has worked for the user and is no longer needed.63 Smokers may have unreasonable expectations of how effective stop-smoking medications are likely to be for them.63 One trial showed that good adherence to varenicline was associated with a two-fold increase in six-month quit rates compared with poor adherence.272 While higher levels of adherence to cessation medications increase the likelihood of sustained smoking cessation, many smokers use them at a lower dose and for less time than is optimal.273  A Cochrane review published in 2019, which assessed the effectiveness of interventions aiming to increase adherence to cessation medications, concluded that there is moderate‐certainty evidence that enhanced behavioural support focusing on adherence to medications can modestly improve adherence. However, the authors only found weak evidence that this may slightly improve the likelihood of cessation in the shorter or longer‐term.274

Smokers’ beliefs about a particular treatment may influence their choice of a particular medication as well as their medication experience.275 A perceived lack of need for cessation aids and beliefs that cessation aids do not help with cessation are consistently associated with medication nonadherence.276 One study found that positive medication expectancies in smokers may contribute to better treatment response, and the authors suggest that assessing treatment expectations and attempting to maintain or improve them may be important for the delivery, evaluation, and targeting of smoking cessation treatments.277 Similarly, participants’ perception of treatment assignment (i.e., their beliefs about whether they have been assigned to receive a medication or a placebo) can also affect treatment outcomes. Participants’ expectancies may therefore influence treatment outcome despite use of placebo-controlled designs. Researchers suggest that inclusion of no-treatment control groups or use of active placebos may be warranted.278

A common ethical concerns about smoking cessation and other randomised controlled trials is whether it is ethical to assign participants to a non-active control condition, thereby denying some participants treatment.279 In a paper addressing such concerns, the authors argue that it is ethical to randomise when it is uncertain whether a new intervention is superior to an older one after benefits, risks, and costs have been taken into account. Other ways of overcoming this problem include a phased study in which all participants received the program eventually; trials with two distinct interventions, each of which serves as the other’s control; trials that allocate high- and low-intensity interventions; and trials that randomise to wait lists.280 A 2020 review also highlighted that interventions provided to comparator/control groups in smoking cessation trials vary substantially which can lead to very different apparent success rates. This makes some cessation interventions appear much more effective than others, whereas the differences in results may be due to a more vs. less effective/intensive comparator group intervention.281 In many health systems, patients seeking clinical care are only offered tobacco treatment if, in the opinion of the clinician, they express a desire to quit smoking or are perceived as ‘ready to quit’. Researchers have proposed that, because only a minority of tobacco users will say they are ready to quit at any given time, all tobacco users should be offered evidence-based care, without being screened for readiness as a precondition for receiving treatment. That is, receiving treatment for tobacco dependence should be ‘opt-out’ rather than ‘opt-in’. They argue that most tobacco users want to quit, there is little to no evidence supporting the utility of assessing readiness to quit, and an opt-out default is more ethical.282 Others have suggested that while this approach may be warranted, a better understanding of its effectiveness and its impact on clinician–patient relationships is needed as a first step.283

Relevant news and research

For recent news items and research on this topic, click  here. ( Last updated June 2024)


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2. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, and Lancaster T. Nicotine replacement therapy versus control for smoking cessation. Cochrane Database of Systematic Reviews, 2018; 5:CD000146. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29852054

3. Howes S, Hartmann-Boyce J, Livingstone-Banks J, Hong B, and Lindson N. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews, 2020; 4:CD000031. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32319681

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