Tobacco smoking continues to be the leading cause of chronic illness and preventable death worldwide
. Around a fifth of all deaths in both the UK and the United States are estimated to be related to smoking, with morbidity and mortality related to respiratory disease, cardiovascular disease and various types of cancer,,
. While smoking rates in some nations are on the decline, overall they remain high worldwide. Average adult male smoking rates in the UK, United States and Australia are around 15–17% compared with 50–60% in Russia and China
. There is also a worrying increase in tobacco consumption in low human development index countries, such as those in sub-Saharan Africa and India
From a treatment perspective, smoking behaviour has a pharmacological impact on several commonly used drugs. This impact can be clinically significant; therefore, the pharmacokinetic and pharmacodynamic impact of smoking should be considered in medicine selection, as well as the introduction and cessation of other therapies. This article aims to outline the considerations pharmacists and other healthcare professionals should be aware of in this context, including the impact of smoking cessation on a drug’s pharmacology and what should be done in practice to avoid the associated effects.
During cigarette smoking, nicotine is inhaled and rapidly absorbed into the pulmonary circulation, reaching the arterial circulation and brain within 10–20 seconds and peak concentration within a few minutes
. When nicotine diffuses into brain tissue it binds to nicotinic cholinergic receptors in the brain, which triggers the release of neurotransmitters (e.g. dopamine, adrenaline, acetylcholine, gamma aminobutyric acid and beta endorphin), and also stimulates the release of the growth hormone, prolactin, and adrenocorticotrophic hormone,
. Subsequently, as nicotine is then promptly distributed to other body tissues, the levels start to decline after around 20–30 minutes.
Long-term cigarette smoking leads to both tolerance and dependence, with smoking becoming a self-medicating and self-regulating behaviour to reduce withdrawal symptoms. Studies have demonstrated that smokers increase their cigarette intake with low-nicotine cigarettes and, in those individuals with urinary acidification, this results in increased nicotine clearance
Tobacco smoking releases carbon monoxide and other toxins, such as polycyclic aromatic hydrocarbons (PAHs), primarily responsible for induction of hepatic enzymes CYP1A2 and CYP2B6, and to a lesser extent CYP3A4 and CYP2C19,
. CYP1A2 is a member of the cytochrome P450 superfamily of hepatic enzymes and is involved in the metabolism of many drugs
. The degree of enzyme induction shows significant inter-individual variability and may be dose dependent, with one study demonstrating dose-dependent increases in CYP1A2 induction with increases in number of cigarettes smoked per day,
. The effects of smoking should be considered in individuals with a smoking rate of more than ten cigarettes per day
. Genetic polymorphisms of the CYP1A2 gene and ethnic differences also contribute to inter-individual variability in both smokers and nonsmokers. Upon smoking cessation, enzyme induction rapidly recovers within days of cessation and reaches a new steady state within one week
The effects of smoking and abrupt smoking cessation are clinically relevant in the management of patients who are treated with a CYP1A2 substrate.
Pharmacokinetic and pharmacodynamic interactions
Tobacco smoking is known to cause interactions with many drugs from different classes. The following sections summarise the clinically relevant pharmacokinetic and pharmacodynamic interactions. A summary of the clinically important pharmacokinetic and pharmacodynamic interactions discussed in these sections can be found in the Table.
Smoking rates are high among people with mental health conditions, compared with the general population
. Epidemiological studies from the UK, United States and Australia have demonstrated lifetime smoking rates up to 50–60% in those with mental health conditions, with the highest incidences occurring during periods of acute exacerbation of psychosis or depression,,
. Therefore, it is highly likely that pharmacy professionals will come into contact with patients who have mental health conditions and who smoke. In addition, they are also highly likely to be in receipt of psychotropic drugs.
The effect of smoking and CYP1A2 induction has been clearly demonstrated with clozapine and olanzapine
. Clozapine is metabolised primarily by CYP1A2 and the difference in enzyme activity accounts for the majority of variance in clozapine metabolism. Drug interactions between clozapine and both inducers and inhibitors of CYP3A4 and CYP2D6 also suggest clearance is mediated in some part by these enzymes
. Therapeutic drug monitoring and pharmacokinetic studies have shown significant decreases in clozapine clearance after smoking cessation,,,,
. Meyer demonstrated a mean increase of clozapine levels of 57% after smoking cessation
, Li et al. showed a 45% mean increase in clozapine clearance
and a meta-analysis by Tsuda et al. demonstrated that the concentration/dose ratio was significantly lower in smokers than in nonsmokers
. Case reports have shown clozapine toxicity upon cessation of smoking
Olanzapine is metabolised primarily by CYP1A2 (50–60% of metabolism) and also via CYP2D6, CYP3A4 and glucuronidation
. Therapeutic drug monitoring studies have shown significantly reduced concentrations of olanzapine in smokers relative to nonsmokers. Gex-Fabry et al. retrospectively reviewed therapeutic drug monitoring data and showed mean concentration reduction of ~12% in smokers compared with nonsmokers
. A prospective therapeutic drug monitoring study showed that steady-state plasma olanzapine concentration/dose ratio closely correlated with CYP1A2 metabolic activity, and described a statistically significant five-fold lower dose-corrected steady-state plasma olanzapine concentration in smokers
. The study authors demonstrated that the mean percentage difference in a standard measure of treatment effectiveness after 15 days of antipsychotic therapy was significantly higher in nonsmokers than in smokers, suggesting treatment effect correlated with drug levels. A meta-analysis by Tsuda et al. of 683 smokers and 451 nonsmokers demonstrated that olanzapine concentration/dose ratio was significantly lower in smokers
. Owing to the rapid decrease in enzyme induction after smoking cessation, patients on clozapine or olanzapine who cease smoking should undergo immediate dose reductions and therapeutic drug monitoring, where available, as a priority. Patients commencing treatment on clozapine and olanzapine should also be routinely counselled about possible drug interactions with smoking and the potential for experiencing adverse events when starting or stopping smoking, so they understand the importance of discussing changes in smoking behaviours with their prescribers.
Risperidone, metabolised by the CYP2B6 pathway, has a lower concentration/dose ratio in smokers; moderate and heavy smokers have been found to require larger doses of risperidone
. Interaction with antipsychotics that are minor substrates for CYP1A2 (e.g. haloperidol, perphenazine and chlorpromazine) may also be possible with smoking, although are likely to be less clinically significant
Antidepressants metabolised via the CYP1A2, CYP2D6 and CYP3A4 pathway have been shown to have decreased serum concentrations in smokers — the best evidence exists for fluvoxamine, mirtazapine, trazodone and duloxetine
. A recent review of therapeutic drug monitoring data demonstrated a reduction in concentration/dose of amitriptyline, escitalopram and mirtazapine in smokers, even when age and sex variables were accounted for
. Although the clinical significance of this remains unclear, it is possible that sudden smoking cessation may increase serum drug concentrations and increase negative side effects (rather than cause toxicity).
Smokers report less sedation on benzodiazepines compared with nonsmokers — a potential pharmacodynamic effect owing to stimulation from nicotine
. Consideration should be given to the potential risk of sedation upon sudden cessation of smoking in patients on benzodiazepines.
Smoking results in both pharmacokinetic and pharmacodynamic interactions with methadone. Methadone is a substrate of CYP2B6, which is induced by PAH exposure in smokers. Nicotine affects the endogenous opioid system, leading to higher concentrations of beta endorphin in nicotine users. Smoking rates in methadone users are high and reduced methadone sedation and higher methadone doses have been shown in smokers,,
. Methadone also attenuates nicotine withdrawal
. Close monitoring should occur when a patient changes smoking status, with dose adjustments made according to individual patient response.
Warfarin is metabolised primarily via CYP2C9 and, to a lesser extent by CYP1A2, CYP2C19 and CYP3A4. A systematic review and meta-analysis of interactions between smoking and warfarin demonstrated an effect of smoking on both warfarin pharmacokinetics and warfarin dose requirement
. A pharmacokinetic study in nine people showed smoking cessation led to a 13% increase in steady-state warfarin concentration, 13% decrease in warfarin clearance and 23% increase in warfarin half-life
. Pooled analysis by Nathisuwan et al. showed that smoking was associated with a 12% increase in warfarin dosage requirement compared with nonsmoking and smokers required 2.26mg more of warfarin per week compared with nonsmokers
. Lenzini et al. compared pharmacogenetic and clinical protocols for warfarin initiation in 265 orthopaedic patients and found that smoking status was a significant predictor of warfarin dose, and included smoking in their therapeutic algorithm
. Patients commencing warfarin therapy should be counselled about the potential smoking–drug interaction and more frequent monitoring should be performed in patients who either commence smoking or suddenly cease smoking.
The thienopyridine P2Y12 inhibitors clopidogrel and prasugrel are converted to their active metabolites by CYP isoenzymes, including CYP1A2, CYP2B6, CYP2C19, CYP3A4/5 and CYP2C9, thus enzyme induction by smoking could theoretically increase the antiplatelet activity of these agents; however, study results in this area are varied,,,
. Park et al. examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response by measuring clopidogrel on-treatment platelet reactivity in 1,431 consecutive patients (smokers n=249) who underwent coronary angiography. They reported an enhanced clopidogrel response in smokers who were carriers of the CYP1A2 (-163C.A) A-allele
The PARADOX study was a prospective, randomised, double-blind, double-dummy, placebo-controlled crossover study of objectively assessed nonsmokers (n=56) and smokers (n=54) with stable coronary artery disease receiving aspirin therapy. The researchers aimed to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel therapy. The results demonstrated higher active metabolite exposure and an increase in platelet inhibition in smokers treated with clopidogrel
. No significant difference was found in prasugrel smokers compared with nonsmokers
Subgroup analysis of 7,062 patients aged <75 years from the primary TRILOGY ACS trial cohort randomised to prasugrel versus clopidogrel were evaluated through 30 months by baseline and time-dependent smoking status. This analysis showed platelet reactivity was lower in current smokers with no significant interaction by treatment with prasugrel versus clopidogrel
. It is difficult to make clinical recommendations in this setting; however, an awareness of these potential interactions in medication prescribing is useful.
In smokers, as with nonsmokers, careful attention should be paid to management of cardiovascular risk factors. Hypertension is a major risk for atherosclerosis by deranging the normal prothrombotic/fibrinolytic balance at the coronary vascular endothelium
. Patients with hypertension should be offered lifestyle modification advice (see Box) plus pharmacotherapy. First-line agents for hypertension include thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers. Current evidence does not support the initial use of beta-blockers for hypertension in the absence of specific cardiovascular comorbidities, such as ischaemic heart disease
Box: Treating hypertension with lifestyle changes
The National Institute for Health and Care Excellence recommends the following lifestyle modifications for the treatment of hypertension:
- Maintain a healthy diet (e.g. eat a variety of fruit and vegetables daily);
- Take regular exercise (adults aged 19–64 years should undertake at least 150 minutes of moderate aerobic activity, such as cycling or brisk walking, every week and strength exercises on two or more days per week that work all the major muscles [e.g. legs, hips, back, abdomen, chest, shoulders and arms]);
- Quit smoking;
- Reduce alcohol intake below 14 units per week (the equivalent of 6 x 175mL glasses of 13% alcohol by volume wine or 6 x 568mL pints of 4% lager or ale);
- Reduce the amount of salt in diet (e.g. cut out salt entirely or use a salt substitute);
- Reduce consumption of caffeinated drinks (e.g. coffee, tea, cola and other soft drinks);
- Relaxation therapies can help to lower blood pressure.
In addition, calcium, magnesium and potassium supplements have traditionally been used to lower blood pressure, but these do not seem to work, so are not recommended.
Sources: https://www.nice.org.uk/guidance/cg127/ifp/chapter/treating-high-blood-pressure-with-lifestyle-changes#diet-and-exercise; https://www.drinkaware.co.uk/alcohol-facts/alcoholic-drinks-units/alcohol-limits-unit-guidelines/
Despite these recommendations, there is some evidence that smokers with hypertension gain additional benefits from first-line beta-blocker therapy that are not seen in the non smoking population
. Cigarette smoking inactivates nitrous oxide (a potent vasodilator) within the vasculature, thereby disrupting endothelial function
. Arterial hypertension separately impairs the coronary vascular endothelium, leading to prothrombotic and hypercoagulable effects. Fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and homocystine (Hcy) are associated with cardiovascular risk via these associated endothelial effects. Vyssoulis et al. studied the effect of vasodilating beta-blockers on endothelial function and prothrombotic state in 550 patients with uncomplicated essential hypertension. They found that smokers have elevated baseline values of fibrinogen, PAI-1 and Hcy compared with nonsmokers. When treated with celiprolol, carvedilol or nebivolol, all parameters were reduced more in smokers than nonsmokers, with nebivolol demonstrating the most favourable effects
. This suggests that smokers may benefit from vasodilating beta-blockers, although this has not yet been demonstrated in terms of cardiovascular end points and mortality data. Further studies are needed before changes to current guidelines can be recommended.
Theophylline, which has a narrow therapeutic window, is predominantly metabolised by CYP1A2 and increased clearance of 60–100% has been demonstrated in smokers,
. Dosage must be individualised and guided by theophylline concentration measurements in smokers and also upon sudden cessation of smoking where theophylline toxicity may occur. Tobacco smoking may also reduce efficacy of inhaled corticosteroids, potentially leading to prolonged exacerbation of asthma
Smoking has been shown to be an independent risk factor for both developing cancer and responding to therapy
. Both nicotine and smoke-related toxins, such as PAHs, have complex pharmacodynamic effects in cancer treatment, with interactions between apoptosis, tumour angiogenesis, host immune function and chemosensitivity
. Pharmacokinetic interactions have been demonstrated with erlotininb and irinotecan, and are postulated in cyclophosphamide and ifosfamide, thus drug interaction between smoking and chemotherapy may also play a role.
A pharmacokinetic study by Hamilton et al. in 32 healthy male subjects aimed to compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150mg or 300mg dose of erlotinib. The authors found that erolotinib and its metabolite OSI-410 demonstrated significantly reduced exposure to erlotinib in smokers, with a 2.8-fold lower area under the curve and a peak serum concentration two-thirds that of nonsmokers
Irinotecan clearance has been shown to be significantly faster in smokers
. Systemic exposure to its active metabolite SN-38 is also lower
. Both of these factors explain the reduction in haematologic toxicity in smokers treated with irinotecan. Irinotecan metabolism is sensitive to CYP3A induction
Cyclophosphamide and ifosfamide
The alkylating chemotherapy agents ifosfamide and cyclophosphamide are metabolised by CYP2B6, 2C9 and 3A4, all of which are induced by smoking
. The effect of smoking on the pharmacokinetics of these agents has not been studied. However, smoking has been identified as an independent risk factor in multiple large studies where cyclophosphamide and/or ifosfamide were involved in therapy. Lamar et al. found smoking to be an independent risk factor for progression-free and overall survival in the treatment of 136 patients with aggressive non-Hodgkin lymphoma on dose adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin with rituximab (DA-EPOCH-R)
. In this study, chemotherapy (including cyclophosphamide) was dose adjusted based on haematological toxicity. A prospective study in 166 patients with soft tissue sarcomas by Gannon et al. found that smoking affected distant metastasis-free survival and progression-free survival in patients with soft tissue sarcoma treated with radiotherapy +/- ifosfamide and doxorubicin
. Further research, including pharmacokinetic studies in smokers versus nonsmokers, is warranted to clarify the impact of smoking on ifosfamide and cyclophosphamide levels, and nicotine’s impact on cancer cell biology and chemosensitivity.
|Pharmacokinetic drug interactions with tobacco smoking and clinical impact|
|Clozapine||Increased clearance of clozapine. Adverse events may occur when smoking is ceased. Doses of clozapine should be reduced when an individual stops smoking.|| ,,,,|
|Olanzapine||Increased clearance of olanzapine. Adverse events may occur when smoking is ceased.|| ,,,,,|
|Fluvoxamine||Increased clearance of fluvoxamine. Smokers may require higher doses.|| ,|
|Warfarin||Smokers may require higher warfarin doses. International normalised ratio monitoring should accompany change in smoking status.|| ,,|
|Theophylline||Increased clearance of theophylline. Toxicity may occur with smoking cessation. Therapeutic drug monitoring is recommended.|| ,|
|Methadone||Smokers may require higher methadone doses. If smoking is ceased, monitor for signs of sedation and assess need for dose reduction.|| ,,,|
|Clopidogrel||Smokers may get higher antiplatelet effect from clopidogrel than nonsmokers.|| ,,,|
|Erlotinib||Increased clearance of erlotinib. Exposure to erlotinib may be decreased in smokers, which should be considered when dosing.|| |
|Irinotecan||Increased clearance of irinotecan. Reduced exposure to irinotecan in smokers may lead to decreased haematological toxicity. Dosing should be closely monitored by oncologist.|| |
|Pharmacodynamic drug interactions with tobacco smoking and clinical impact|
|Benzodiazepines||Lower sedation in smokers. If smoking is ceased, monitor for signs of sedation.|| |
|Methadone||Nicotine affects the endogenous opioid system. Methadone users report increased and reduced sedation when smoking. Clinical monitoring needed with any change in smoking status.|| ,,|
Pharmacotherapies used to support smoking cessation
Smoking cessation is associated with great benefits to health and should be routinely recommended by pharmacists and other healthcare professionals. At the time of smoking cessation, pharmacists should give consideration to its pharmacokinetic effects, as outlined above, along with the potential drug interactions with pharmacotherapies used to help the person abstain from cigarettes. The CYP1A2 induction that occurs with cigarette smoking is owing to PAHs in tobacco smoke, not the nicotine itself,
. Therefore, this enzyme induction will not occur in patients receiving nicotine replacement therapy (NRT) and dosing adjustments should take place accordingly
Stopping smoking can be difficult and only around 5% of those who try to quit without professional support remain abstinent at one year. Assistance with smoking cessation includes behavioural support, NRT and other pharmacotherapies
. Recommended pharmacotherapies for smoking cessation include NRT, varenicline and bupropion. For optimal outcomes, varenicline should be used for at least 12 weeks and NRT or bupropion for a minimum of 8 weeks
Bupropion, a selective catecholamine reuptake inhibitor, reverses the negative effect associated with nicotine withdrawal
. Bupropion is associated with an infrequent but possible dose-related risk of seizures. Using other drugs that lower the seizure threshold, or concurrently reducing benzodiazepines or other antiseizure medications, increases this risk of seizures. Bupropion is metabolised by CYP2B6 to hydroxybupropion and other metabolites. Co-administration of drugs known to induce CYP2B6 metabolism (e.g. carbamazepine and phenytoin) or inhibit metabolism through a phase II process (e.g. valproate) may affect the activity of bupropion.
Bupropion acts as an inhibitor in the CYP2D6 pathway, a common metabolic pathway for many antidepressant and antipsychotic medicines including venlafaxine and tricyclic antidepressants. Metoprolol, tramadol, methadone and several other cardiovascular and analgesic medicines are also substrates of CYP2D6 and dosages may need to be reduced if bupropion is prescribed
. There have been case reports of delirium in patients where bupropion was prescribed with risperidone
, possibly owing to impaired metabolism of hydroxybupropion, a CYP2D6 substrate.
Varenicline binds with high affinity and selectivity at the Î±4Î²2 neuronal nicotinic acetylcholine receptor, where it acts as a partial agonist and relieves nicotine withdrawal symptoms
. Its binding both alleviates symptoms of craving and withdrawal, and reduces the rewarding and reinforcing effects of smoking by preventing nicotine binding to Î±4Î²2 receptors
. To date, varenicline has no known clinically significant drug interactions
. Concern about severe psychiatric and cardiac side effects have been studied through US Food and Drug Administration post-marketing randomised control trials (RCTs).
A multinational RCT of more than 8,000 smokers found no significant increase in rates of moderate-to-severe neuropsychiatric adverse events with either varenicline or bupropion relative to nicotine patch or placebo in those with or without psychiatric disorders (although the trial excluded patients with symptomatically unstable psychiatric conditions)
. While this study did not specifically look at drug interactions, over 45% of the psychiatric cohort were on psychotropic medicines and it was reported that adverse event rates with NRT, bupropion and varenicline were comparable to placebo
. A non-treatment extension phase of this study examined rate and onset of cardiovascular events and found no significant difference in time to onset of major adverse cardiovascular events with varenicline or bupropion versus placebo
. Although these studies were not designed to investigate pharmacological interactions, the findings may help to reassure those concerned about pharmacodynamic interactions adversely affecting the psychiatric or cardiovascular health of patients.
E-cigarettes are vapourising devices that heat a liquid in a cartridge or reservoir into an aerosol for inhalation. The substance contained in the electronic cigarette may contain varying amounts of nicotine or other chemicals with the purpose of providing different flavours. Owing to this lack of standardisation, it is not possible to make categorical statements about the chemical properties or safety of e-cigarettes
. Based on the available information, e-cigarettes are currently considered safer than conventional cigarettes
Smoking induces a number of enzymes that affect drug metabolism. Smoking cessation leads to prompt reversal of enzyme induction, which leads to significantly altered drug concentrations. Smoking cessation should always be encouraged and supported; however, prescribers should also give careful consideration to the doses of medicines that are metabolised via CYP1A2 and CYP2B6 in smokers, particularly when a person ceases smoking. Therapeutic drug monitoring, where available, should also be considered. NRT and varenicline may be used to increase chances of successful cessation and do not have any known significant drug–drug interactions. Bupropion is another option for smoking cessation, but this drug has multiple potential interactions that should be taken into consideration at initiation and cessation of therapies.
Financial and conflicts of interest disclosure
The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was used in the production of this manuscript.
 World Health Organization. WHO global report on trends in tobacco smoking 2015. Tobacco Free Initiative. Available at: http://www.who.int/tobacco/publications/surveillance/reportontrendstobaccosmoking/en/index4.html (accessed January 2019)
 Office for National Statistics. Adult smoking habits in the UK: 2017. 2018. Available at: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/adultsmokinghabitsingreatbritain/2017 (accessed January 2019)
 Australian Bureau of Statistics. National Health Survey: First results, 2014–2015. 2015. ABS Catalogue No. 4364.0.55.001. Available at: http://www.abs.gov.au/AUSSTATS/abs@.nsf/DetailsPage/4364.0.55.0012014-15?OpenDocument (accessed January 2019)
 Drope J, Schluger N, Cahn Z et al. The Tobacco Atlas: Sixth Edition. 2018. Available at: https://tobaccoatlas.org/wp-content/uploads/2018/03/TobaccoAtlas_6thEdition_LoRes_Rev0318.pdf (accessed January 2019)
 Le Houezec J. Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review. Int J Tuberc Lung Dis 2003;7(9):811–819. PMID: 12971663
 Mendelson JH, Sholar MB, Goletiani N et al. Effects of low- and high-nicotine cigarette smoking on mood states and the HPA axis in men. Neuropsychopharmacology 2005;30(9):1751–1763. doi: 10.1038/sj.npp.1300753
 Benowitz NL. Risks associated with smoking cigarettes with low machine-measured yields of tar and nicotine. Chapter 3: Compensatory smoking of low-yield cigarettes. Smoking and Tobacco Control Monograph No. 13. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 2001. Available at: https://cancercontrol.cancer.gov/brp/TCRB/monographs/13/m13_complete.pdf (accessed January 2019)
 Faber MS, Jetter A & Fuhr U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol 2005;97(3):125–134. doi: 10.1111/j.1742-7843.2005.pto_973160.x
 Tantcheva-PoÃ³r I, Zaigler M, Rietbrock S & Fuhr U. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics 1999;9(2):131–144. PMID: 10376760
 Zhou SF, Yang LP, Zhou ZW et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J 2009;11(3):489–491. doi: 10.1208/s12248-009-9127-y
 Faber MS & Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther 2004;76(2):178–184. doi: 10.1016/j.clpt.2004.04.003
 Greenhalgh EM, Stillman S, & Ford C. 7.12 Smoking and mental health. In: Scollo MM & Winstanley MH [Eds]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria. 2018. Available at: http://www.tobaccoinaustralia.org.au/chapter-7-cessation/7-12-smoking-and-mental-health (accessed January 2019)
 Lawrence D, Mitrou F & Zubrick SR. Smoking and mental illness: results from population surveys in Australia and the United States. BMC Public Health 2009;9:285. doi: 10.1186/1471-2458-9-285
 Lasser K, Boyd JW, Woolhandler S et al. Smoking and mental illness: A population-based prevalence study. JAMA 2000;284(20):2606–2610. doi: 10.1001/jama.284.20.2606
 Tsuda Y, Saruwatari J & Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open 2014;4(3):e004216. doi: 10.1136/bmjopen-2013-004216
 Meyer JM. Individual changes in clozapine levels after smoking cessation: results and a predictive model. J Clin Psychopharmacol 2001;21(6):569–574. doi: 10.1097/00004714-200112000-00005
 Å agud M, Vuksan-Äusa B, JakÅ¡iÄ N et al. Smoking in schizophrenia: An updated review. Psychiatr Danub 2018;30(4):216–223. PMID: 29864763
 Li L, Shang D, Li W et al. Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia. Acta Pharmacol Sin 2012;33(11):1409–1416. doi: 10.1038/aps.2012.71
 Zullino DF, Delessert D, Eap CB et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol 2002;17(3):141–143. doi: 10.1097/00004850-200205000-00008
 Gex-Fabry M, Balant-Gorgia AE & Balant LP. Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit 2003;25(1):46–53. doi: 10.1097/00007691-200302000-00007
 Carillo JA, Herraiz AG, Ramos SI et al. Rose of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003;23(2):119–127. doi: 10.1097/00004714-200304000-00003
 Schoretsanitis G, Haen E, Stegmann B et al. Effect of smoking on risperidone pharmacokinetics — a multifactorial approach to better predict the influence on drug metabolism. Schizophr Res 2017;185:51–57. doi: 10.1016/j.schres.2016.12.016
 Hiemke C, Bergemann N, Clement HW et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018;51(1–2):9–62. doi: 10.1055/s-0043-116492
 Oliveira P, Ribeiro J, Donata H & Madeira N. Smoking and antidepressants pharmacokinetics: a systematic review. Ann Gen Psychiatry 2017;16:17. doi: 10.1186/s12991-017-0140-8
 Scherf-Clavel M, Samanski L, Burger R et al. Differences in the pharmacokinetics of psychopharmacological drugs between smokers and nonsmokers. Pharmacopsychiatry 2018;51(03):113–118. doi: 10.1055/s-0038-1649541
 Olivier D, Lubman DI & Fraser R. Tobacco smoking within psychiatric inpatient settings: biopsychosocial perspective. Aust N Z J Psychiatry 2007;41(7):572–580. doi: 10.1080/00048670701392809
 Elkader AK, Brands B, Selby P & Sproule BA. Methadone-nicotine interactions in methadone maintenance treatment patients. J Clin Psychopharmacol 2009;29(3):231–238. doi: 10.1097/JCP.0b013e3181a39113
 Chait LD & Griffiths RR. Effects of methadone on human cigarette smoking and subjective ratings. J Pharmacol Exp Ther 1984;229(3):636–640. PMID: 6726650
 Do HP, Nguyen LH, Thi Nguyen NP et al. Factors associated with nicotine dependence during methadone maintenance treatment: findings from a multisite survey in Vietnam. BMJ Open 2017;7(7):e015889. doi: 10.1136/bmjopen-2017-015889
 Nathisuwan S, Dilokthornsakul P, Chaiyakunapruk N et al. Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis. Chest 2011;139(5):1130–1139. doi: 10.1378/chest.10-0777
 Bachmann K, Shapiro R, Fulton R et al. Smoking and warfarin disposition. Clin Pharmacol Ther 1979;25(3):309–315. doi: 10.1002/cpt1979253309
 Lenzini PA, Grice GR, Milligan PE et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopaedic patients. J Thromb Haemost 2008;6(10):1655–1662. doi: 10.1111/j.1538-7836.2008.03095.x
 Wang ZY, Chen M, Zhu LL et al. Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy. Ther Clin Risk Manag 2015;11:449–467. doi: 10.2147/TCRM.S80437
 Park KW, Park JJ, Jeon K-H et al. Enhanced clopidogrel responsiveness in smokers: smokers’ paradox is dependent on cytochrome P450 CYP1A2 status. Arterioscler Thromb Vasc Biol 2011;31(3):665–671. doi: 10.1161/ATVBAHA.110.217182
 Gurbel PA, Bliden KP, Logan DK et al. The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: The PARADOX Study. J Am Coll Cardiol 2013;62(6):505–512. doi: 10.1016/j.jacc.2013.03.037
 Cornel JH, Ohman EM, Neely B et al. Impact of smoking status on platelet function and clinical outcomes with prasugrel vs. clopidogrel in patients with acute coronary syndromes managed without revascularization: insights from the TRILOGY ACS trial. Am Heart J 2014;168(1):76–87. doi: 10.1016/j.ahj.2014.04.011
 Vyssoulis GP, Marinakis AG, Aznaouridis KA et al. The impact of third-generation beta-blocker antihypertensive treatment on endothelial function and the prothrombotic state: effects of smoking. Am J Hypertens 2004;17(7):582–589. doi: 10.1016/j.amjhyper.2004.03.668
 Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation and management of high blood pressure in adults. J Am Coll Cardiol 2018;71(19):e127–e248. doi: 10.1016/j.jacc.2017.11.006
 Schmidt AC, Flick B, Jahn E & Bramlage P. Effects of the vasodilating beta-blocker nebivolol on smoking-induced endothelial dysfunction in young healthy volunteers. Vasc Health Risk Manag 2008;4(4):909–915. doi: 10.2147/vhrm.s3020
 Thomson NC, Chaudhuri R & Livingston E. Asthma and cigarette smoking. Eur Respir J 2004;24(5):822–833. doi: 10.1183/09031936.04.00039004
 Goseva Z, Gjorcev A, Kaeva BJ et al. Analysis of plasma concentrations of theophylline in smoking and nonsmoking patients with asthma. Open Access Maced J Med Sci 2015;3(4):672–675. doi: 10.3889/oamjms.2015.117
 Sanner T & Grimsrud TK. Nicotine: carcinogenicity and effects on response to cancer treatment – a review. Front Oncol 2015;5:196. doi: 10.3389/fonc.2015.00196
 Hamilton M, Wolf JL, Rusk J et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 2006;12(7 Pt 1):2166–2171. doi: 10.1158/1078-0432.CCR-05-2235
 Van der Bol JM, Mathijssen RH, Loos WJ et al. Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 2007;25(19):2719–2726. doi: 10.1200/JCO.2006.09.6115
 Roy P, Yu LJ, Crespi CL & Waxman DJ. Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999;27(6):655–666. PMID: 10348794
 Lamar ZS, Fino N, Palmer J et al. Infusional etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone +/- rituximab as first-line therapy for aggressive non-Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2016;16(2):76–81. doi: 10.1016/j.clml.2015.11.012
 Gannon NP, King DM & Bedi M. Smoking is predictive of poorer distant metastasisâfree and progression freeâsurvival in soft tissue sarcoma patients treated with pre-operative radiotherapy or chemoradiotherapy. Clin Sarcoma Res 2018;8:7. doi: 10.1186/s13569-018-0088-8
 Lucas CJ & Martin JH. Smoking and drug interactions. Australian Prescriber 2013;36:102–104. doi: 10.18773/austprescr.2013.037
 Hartmann-Boyce J, McRobbie H, Bullen C et al. Electronic cigarettes for smoking cessation. Cochrane Database Syst Rev 2016;9:CD010216. doi: 10.1002/14651858.CD010216.pub3
 National Institute for Health and Care Excellence. Smoking: supporting people to stop. August 2013. Available at: https://www.nice.org.uk/guidance/qs43/ (accessed January 2019)
 Motooka Y, Matsui T, Slaton RM et al. Adverse events of smoking cessation treatments (nicotine replacement therapy and non-nicotine prescription medication) and electronic cigarettes in the Food and Drug Administration Adverse Event Reporting System, 2004-2016. SAGE Open Med 2018;6:I–II. doi: 10.1177/2050312118777953
 Lucas CJ, Patel J & Martin JH. Predicting drug interactions in addiction treatment. Intern Med J 2017;47(8):872–878. doi: 10.1111/imj.13500
 Lu YY, Hsueh JH, Wei IH & Huang CC. Delirium caused by drug-drug interaction between bupropion and risperidone. J Clin Psychopharmacol 2014;34:161–162. doi: 10.1097/JCP.0b013e3182a60862
 Ma SP, Tsai CJ, Chang CC & Hsu WY. Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient. Psychogeriatrics 2017;17:130–132. doi: 10.1111/psyg.12202
 National Institute for Health and Care Excellence. Varenicline for smoking cessation. 2007. Available at: https://www.nice.org.uk/guidance/ta123/ (accessed January 2019)
 FagerstrÓ§m K & Hughes J. Varenicline in the treatment of tobacco dependence. Neuropsychiatr Dis Treat 2008;4(2):353–363. doi: 10.2147/ndt.s927
 Athenelli RM, Benowitz NL, West W et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 2016;387:2507–2520. doi: 10.1016/S0140-6736(16)30272-0
 Benowitz NL, Pipe A, West W et al. Cardiovascular safety of varenicline, bupropion, and nicotine patch in smokers. JAMA Intern Med 2018;178(5):622–631. doi: 10.1001/jamainternmed.2017.6015
 Tobacco Advisory Group of the Royal College of Physicians. Nicotine without smoke: Tobacco harm reduction. 2016. https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0 (accessed January 2019)