Cardiovascular and neuropsychiatric safety of smoking cessation pharmacotherapies in non-depressed adults: a retrospective cohort study

Addiction. 2020 Aug;115(8):1534-1546. doi: 10.1111/add.14951. Epub 2020 Feb 19.


Background and aims: Pharmacotherapies for smoking cessation are widely prescribed, despite substantial concerns being raised regarding the potential increased risk of cardiovascular (CV) and neuropsychiatric adverse events associated with these treatments. This study aimed to assess the relative CV and neuropsychiatric safety between varenicline and bupropion compared with nicotine replacement therapies (NRT) in adults without a recent history of depression.

Design: Retrospective new-user cohort study.

Setting: US administrative data from 2006 to 2016 covering more than 100 million individuals.

Participants: Three study cohorts of new users, aged 18 years or older, limited to patients with no diagnosis or treatment for depression in the prior 12 months.

Measurements: Propensity score adjusted log-binomial regression models. The primary outcome was a composite of hospitalized CV events. Secondary outcomes included a composite of hospitalized neuropsychiatric events and individual components of the primary outcome.

Findings: A total of 618 497 participants were included in our study cohorts. Compared with NRT (n = 32 237), varenicline (n = 454 698) was associated with a 20% lower 1-year CV risk [adjusted relative risk (RR) = 0.80, 95% confidence interval (CI) = 0.75-0.85], and bupropion (n = 131 562) was associated with a 25% lower 1-year CV risk (RR = 0.75, 95% CI = 0.69-0.81). Varenicline was associated with a 35% lower 1-year risk of neuropsychiatric hospitalization versus NRT (RR = 0.65, 95% CI = 0.59-0.72), and bupropion was associated with a 21% increase in 1-year risk of neuropsychiatric hospitalization (RR = 1.21, 95% CI = 1.09-1.35).

Conclusion: Varenicline compared with nicotine replacement therapy does not appear to be associated with an increased risk of cardiovascular or neuropsychiatric hospitalizations. Bupropion appears to be associated with a lower risk of cardiovascular hospitalization and a higher risk of neuropsychiatric hospitalization, compared with nicotine replacement therapy.

Keywords: Addiction; cardiovascular; health risk; neuropsychiatric; nicotine dependence; observational research; pharmacology; population health; smoking cessation; tobacco.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bupropion / adverse effects
  • Cardiovascular Diseases / epidemiology*
  • Cohort Studies
  • Female
  • Humans
  • Male
  • Mental Disorders / epidemiology*
  • Middle Aged
  • Nicotinic Agonists / adverse effects
  • Retrospective Studies
  • Smoking Cessation / methods*
  • Smoking Cessation Agents / adverse effects
  • Tobacco Use Cessation Devices / adverse effects
  • Tobacco Use Disorder / drug therapy*
  • United States / epidemiology
  • Varenicline / adverse effects
  • Young Adult


  • Nicotinic Agonists
  • Smoking Cessation Agents
  • Bupropion
  • Varenicline