Tobacco Smoking and its Drug Interactions in Psychiatric Populations: Implications for Inpatient Care

Vol 11 #3 January 13, 2022

Cynthia H. Chan, HBSc1, Ana Hategan, MD2,

Author information

1  Medical Student,  Michael G. DeGroote School of Medicine, Faculty of Health Sciences,  McMaster University, Hamilton, Ontario, Canada

2  Clinical Professor, Geriatric Psychiatrist, Division of Geriatric Psychiatry, Department of Psychiatry and Behavioural Neurosciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. ✉ [email protected] ORCID iD



This narrative review provides an overview of relevant literature regarding pharmacokinetic and pharmacodynamic considerations during acute hospitalization and discharge planning, emphasizing the need for medication dose adjustment in patients with smoking behaviour. This review aims to increase awareness regarding drug monitoring as a tool to optimize drug safety and provide individual tailored therapy in smokers, particularly in psychiatric populations.


Pharmacokinetic and Pharmacodynamic Considerations

The smoking habits of patients are virtually always assessed upon hospital admission. This information is valuable because it can increase clinical suspicion for diagnoses with known associations with smoking and it may allow for appropriate nicotine replacement therapies in smoke-free hospital settings. However, there is much more to it than that.

Tobacco smoking produces polycyclic aromatic hydrocarbons, which induce the expression of drug-metabolizing enzymes including cytochrome P450 (CYP) 1A1 (an extrahepatic enzyme present in lungs and placenta) and CYP1A2 (a hepatic enzyme) (Fankhauser, 2013; Kroon, 2007). There is also evidence that the expression of CYP2E1 isoenzyme is also induced, as seen in animal models (Fankhauser, 2013; Kroon, 2007). However, the association between smoking and CYP2E1 expression is unclear. Individuals exposed to second-hand smoke may also have changes in drug metabolism due to induction of hepatic CYP1A2 (Kroon, 2007). As nicotine replacement therapy does not produce polycyclic aromatic hydrocarbons, it does not lead to increased CYP expression.

CYP1A1, CYP1A2, and CYP2E1 participate in the metabolism of drugs, thus their expression may affect the plasma concentration and half-life of medications which act as substrates for these enzymes. This may cause individuals with tobacco smoke exposure (e.g., individuals who smoke or have second-hand smoke exposure) to require higher medication doses as compared to their non-exposed counterparts. This effect is demonstrated in a study by Hunt et al (1976) which found that theophylline, a known substrate of CYP1A2, has a significantly shorter half-life in “heavy” smokers (1 to 2 packs per day) as compared to non-smokers. This study also found that four heavy smokers who refrained from smoking for at least 3 months experienced no significant change in theophylline clearance. The authors suspected this reflects that the enzymes involved in theophylline metabolism do not readily normalize to non-smoking levels within three months of smoking cessation. A subsequent study by Faber and Fuhr (2004) assessed CYP1A2 levels in “heavy” smokers (20 or more cigarettes per day). This study found an exponential decrease in CYP1A2 expression in the days following smoking cessation, which reached a steady state after approximately one week. This is in keeping with the half-life of CYP1A2 of 38.6 hours. Though there may be variability in the literature regarding hepatic metabolism returning to non-smoking levels following smoking cessation, the findings from Faber and Fuhr (2004) suggest that brief admissions to smoke-free hospitals (surgical, medical, or psychiatric units) can lead to acute changes in drug metabolism.

A study by Swett (1974) investigated the relationship between the intensity of tobacco smoking and metabolism of chlorpromazine by comparing a chlorpromazine side effect (drowsiness) in non-smokers, “light” smokers (20 or fewer cigarettes per day), and “heavy” smokers (more than 20 cigarettes per day). This study found a significant negative association between drowsiness and intensity of smoking. This was true at different doses of chlorpromazine. The study author proposes that this negative association is the result of tobacco smoke inducing enzymes which metabolize chlorpromazine (Swett, 1974). Since chlorpromazine is a known substrate of CYP1A2, this study supports a dose-dependent effect of tobacco smoke exposure and increased hepatic drug metabolism. These findings suggest that individuals with greater intensities of tobacco smoking should be more closely monitored during hospital admissions where they refrain from smoking.

For patients admitted to a smoke-free institution, decreased tobacco smoke exposure can lead to decreased drug metabolism as CYP1A1, CYP1A2, and possibly CYP2E1 expression normalize to non-smoking levels. If the dosages of patients’ medications are not adjusted to factor in this change, patients may receive a higher dose than required for the intended clinical purpose. Furthermore, in patients who resume smoking following discharge, the dose of medications prescribed during their admission may become insufficient.

A list of common medications which are substrates of CYP1A1, CYP1A2, and CYP2E1 is provided in Table 1 (Rendic, 2002). However, a negative association between tobacco smoke and the metabolism of these drugs is not clinically observed for each drug presented in Table 1. An important pharmacodynamic consideration is that a drug may act as both substrate and inhibitor of CYP proteins. Additionally, patients may concurrently take medications which are substrates and inhibitors. The complexity of the pharmacokinetics and pharmacodynamics of these medications requires more research to inform the necessary dose adjustments of individual medication for patients as their exposure to tobacco smoke changes.

Table 1. Common substrates of CYP1A1, CYP1A2, and CYP2E1

Psychotropic drugs
Abecarnil Amitriptyline Bupropion
Clomethiazole Chlorpromazine Fluoxetine
Diclofenac Acetaminophen Acetaminophen
Diclofenac Salicylates
Cardiovascular drugs
Amiodarone Bufuralol Carvedilol
Carvedilol Carvedilol Nicardipine
Nicardipine Cilostazol Norverapamil
Propranolol Dihydralazine Quinidine
Warfarin Nicardipine Verapamil
Caffeine Caffeine Caffeine
Estradiol Estradiol Estradiol
Estrone Estrone Estrone
Progesterone Progesterone Nicotine
Testosterone Ropinirole Theophylline
Theophylline Selegiline

Data extracted from Rendic (2002).

Practice Considerations for Acute Care

The implications of the interactions between medications and tobacco smoking are important to all patient populations but are particularly clinically relevant to psychiatric populations. A report by the Centres for Disease Control and Prevention released in 2013 using data from the 2009-2011 National Survey on Drug Use and Health (NSDUH) revealed that 36.1% of adults aged 18 and older in the U.S.A. with any psychiatric illness (defined as having an emotional disorder in the past 12 months, excluding developmental and substance use disorders) were current smokers (Gfroerer et al, 2013). This number is 75% greater than the percentage of U.S. adults aged 18 and older who were reported to be current smokers in the 2009 National Health Interview Survey (20.6%) (Dube, 2010). According to the 2009-2011 NSDUH survey, adults with any psychiatric illness smoked 30.9% of all cigarettes smoked by adults. Moreover, adult smokers with psychiatric illnesses are less likely to quit smoking than adult smokers without psychiatric illnesses (Gfroerer et al, 2013).

In addition to increased rates of tobacco use disorder, previous studies suggest that patients with psychiatric illnesses are more likely to have chronic systemic medical comorbidities as compared to the general population. A review of non-psychiatric hospitalizations found that patients with psychiatric illnesses are also more likely to be hospitalized and experience prolonged hospital stays as compared to patients without psychiatric illnesses (Zolnierek, 2009). Taken together, increased rates of smoking and increased hospitalization suggest that patients with psychiatric illnesses are more likely to experience changes in their drug metabolism due to smoking cessation during admission to smoke-free hospitals. Furthermore, pharmacokinetic interactions with smoking are expected to occur with many psychotropic drugs that are CYP1A2 substrates (e.g., olanzapine, clozapine, perphenazine, chlorpromazine, fluvoxamine, nortriptyline, mirtazapine) (See Table 1). Altogether, this suggest that psychiatric patients with tobacco use disorder, particularly those with multimorbidity (coexistence of two or more chronic health conditions) and polypharmacy (regular use of at least 5 medications), are more vulnerable to receiving inappropriate medication doses during acute hospital admission and following discharge.

Drug Dose Adjustment

Smokers taking a medication that interacts with tobacco smoke may require higher dosages than non-smokers. Upon smoking cessation (including during admission to a smoke-free inpatient setting), smokers may require a reduction in the dosage of an interacting medication. Faber and Fuhr (2004) propose a stepwise 10% daily dose reduction for CYP1A2 substrates until the fourth day of smoking cessation due to the exponential decrease in CYP1A2 expression following cessation in heavy smokers. CYP1A2 substrates with narrow therapeutic indices (e.g., clozapine) should have doses decreased immediately upon cessation of heavy smoking (Faber & Fuhr, 2004; Moschny et al, 2021).

As previously noted, there is variation in drug metabolism among the substrates of CYP proteins. As such, therapeutic drug monitoring where feasible (e.g., clozapine, olanzapine, and nortriptyline plasma levels) should be performed to ensure an appropriate clinical response to dose adjustments. Unfortunately, no studies have been performed to investigate the time course of CYP1A1 and CYP2E1 following smoking cessation. Therefore, it is difficult to make recommendations for dose adjustment. In patients with changes to tobacco smoke exposure, it would likely be appropriate to monitor the therapeutic effect of CYP1A1 and CYP2E1 substrates in the days following the change.

Takeaway Points

  • Increased awareness is needed about the high prevalence of tobacco smoking among adults with psychiatric illnesses; therefore, enhanced efforts to reduce adverse effects caused by non-therapeutic drug doses in patients with change in their smoking behaviour are warranted.
  • Numerous drug interactions exist with tobacco smoke exposure.
  • After an individual refrains from smoking, an important consideration is how quickly the induction of CYP1A2 dissipates.
  • Although this is debatable, some report that an exponential decrease in CYP1A2 expression in the days following smoking cessation is to be expected, which may reach a steady state after approximately one week (Faber & Fuhr, 2004).
  • In smokers, pharmacotherapy with psychotropic drugs, such as antidepressants and antipsychotics used in the treatment of depressive, bipolar, and psychotic disorders, should be closely monitored due to various factors (e.g., the narrow therapeutic range of certain psychotropic agents, the common occurrence of polypharmacy in psychiatry, the chronicity of most severe psychiatric illnesses).
  • Therapeutic drug monitoring in those with smoking behaviour (those who smoke or have significant exposure through second-hand smoking) may aid with drug titration by enabling the quantification of patients’ drug plasma levels, particularly during acute admissions (Moschny et al, 2021).


The authors report no financial relationships with any companies whose products are mentioned in this article, or with companies of competing products.



Dube, S. R., McClave, A., James, C., Caraballo, R., Kaufmann, R., & Pechacek, T. (2010, September 10). Vital Signs: Current Cigarette Smoking Among Adults Aged ≥18 Years – United States, 2009. Centers for Disease Control and Prevention. Retrieved January 8, 2022, from

Faber, M. S., & Fuhr, U. (2004). Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clinical Pharmacology & Therapeutics, 76(2), 178–184.

Fankhauser, M. P. (2013). Drug interactions with tobacco smoke: Implications for patient care. Current Psychiatry, 12(1), 12–16.

Gfroerer, J., Dube, S. R., King, B. A., Garrett, B. E., Babb, S., & McAfee, T. (2013, February 8). Vital signs: Current cigarette smoking among adults aged ≥18 years with mental illness – United States, 2009–2011. Centers for Disease Control and Prevention. Retrieved January 8, 2022, from

Hunt, S. N., Jusko, W. J., & Yurchak, A. M. (1976). Effect of smoking on theophylline disposition. Clinical Pharmacology & Therapeutics, 19(5part1), 546–551.

Kroon, L. A. (2007). Drug interactions with smoking. American Journal of Health-System

Pharmacy, 64(18), 1917–1921.

Moschny, N., Hefner, G., Grohmann, R., Eckermann, G., Maier, H. B., Seifert, J., Heck, J., Francis, F., Bleich, S., Toto, S., & Meissner, C. (2021). Therapeutic drug monitoring of second- and third-generation antipsychotic drugs—influence of smoking behavior and inflammation on pharmacokinetics. Pharmaceuticals, 14(6), 514.

Rendic, S. (2002). Summary of information on human CYP enzymes: Human P450 metabolism data. Drug Metabolism Reviews, 34(1-2), 83–448.

Swett, C. (1974). Drowsiness due to chlorpromazine in relation to cigarette smoking. Archives of General Psychiatry, 31(2), 211.

Zolnierek, C. D. (2009). Non-psychiatric hospitalization of people with mental illness: Systematic review. Journal of Advanced Nursing, 65(8), 1570–1583.

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