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Top Antidepressants to Quit Smoking: Bupropion & Nortriptyline (2023 Evidence Review)

In the ever-evolving fight against tobacco addiction, the potential of antidepressants, particularly bupropion and nortriptyline, as smoking cessation aids has come into sharp focus.

A comprehensive review evaluated the efficacy, potential harms, and tolerability of these medications, providing insights into their role in helping smokers quit.


  • Bupropion significantly increases the chances of long-term smoking cessation, with a 49% to 72% improvement over placebo or no treatment.
  • The combination of bupropion and varenicline might offer higher quit rates than either treatment alone, although the evidence is more substantial for bupropion’s standalone efficacy.
  • Antidepressants, while effective, may increase the risk of non-serious and serious adverse events, particularly psychiatric ones.
  • There’s a lack of evidence supporting the effectiveness of other antidepressants like SSRIs for smoking cessation, positioning bupropion and nortriptyline as more favorable options.

Source: Cochrane Library (2023)

Tobacco, Cigarette, Nicotine Addiction (Basics) & Antidepressants

Understanding Tobacco Addiction

Tobacco use remains one of the leading preventable causes of death worldwide.

Nicotine, the primary addictive component of tobacco, hijacks the brain’s reward system, making quitting a formidable challenge for many.

Over the years, various strategies have been employed to help individuals quit smoking, ranging from behavioral therapies to pharmacological interventions.

Antidepressants as a Beacon of Hope

Antidepressants, particularly those affecting the dopamine and serotonin pathways, have emerged as potential allies in the battle against nicotine addiction.

Their ability to alleviate withdrawal-induced low mood and potentially modify neural pathways related to addiction makes them a subject of keen interest.

Evidence Review of Antidepressants for Quitting Smoking (2023)

The study was conducted with the primary aim of providing a thorough and updated understanding of the efficacy, potential harms, and tolerability of antidepressants used for smoking cessation.

Why the Study Was Conducted:

  • Health Imperative: Smoking is a global health crisis, and effective cessation strategies are crucial. Antidepressants offered a promising avenue due to their impact on mood and potential to alleviate withdrawal symptoms, but a thorough assessment was needed to validate their use.
  • Addressing the Knowledge Gap: Prior research provided some insights into the role of antidepressants in smoking cessation, but there were gaps in understanding their overall efficacy and safety profile. A systematic review was necessary to consolidate existing data and bring clarity to the topic.
  • Guiding Clinical Practice: Clinicians needed evidence-based guidance on prescribing antidepressants for smoking cessation. The study aimed to provide comprehensive data to inform clinical decisions and ensure the best outcomes for individuals attempting to quit smoking.
  • Informing Public Health Policies: By evaluating the effectiveness and safety of antidepressants as cessation aids, the study aimed to inform public health policies and strategies for tobacco control.

Study Methods:

  • Systematic Literature Search: A systematic search of the Cochrane Tobacco Addiction Group Specialised Register was conducted. This approach was designed to capture all relevant studies, ensuring a comprehensive review of the available evidence.
  • Inclusion Criteria: The study focused on randomized controlled trials (RCTs), the gold standard for clinical research, to ensure the highest level of evidence. It included studies that compared antidepressants with placebo, no pharmacological treatment, other pharmacotherapies, or different dosages of the same medication in people who smoked.
  • Long-Term Focus: Recognizing that short-term cessation does not necessarily translate to permanent abstinence, the study included trials with at least six months of follow-up for efficacy analyses. This approach ensured that the findings were relevant for long-term smoking cessation.
  • Comprehensive Outcome Measures: The study didn’t just look at the effectiveness of the medications in aiding smoking cessation; it also thoroughly examined potential harms and tolerability. This included a wide range of adverse events, serious adverse events, psychiatric issues, and more, providing a holistic view of the medications’ impact.
  • Rigorous Data Analysis: Data were meticulously extracted and analyzed using standard Cochrane methods. This included a risk of bias assessment for each study, ensuring that the findings were reliable and valid.
  • Sensitivity and Certainty Assessments: The study included sensitivity analyses to understand the impact of high-risk studies and used the GRADE approach to assess the certainty of the evidence. These steps added layers of rigor and confidence to the findings.

Best Antidepressants to Quit Smoking? Bupropion & Nortriptyline

Bupropion’s Role in Smoking Cessation

High-certainty evidence indicates that bupropion significantly improves quit rates compared to placebo or no pharmacological treatment.

The addition of bupropion to varenicline, a non-antidepressant smoking cessation aid, might further enhance quitting success, although the evidence for adding it to nicotine replacement therapy (NRT) is less clear.

Nortriptyline’s Contribution

While not as extensively studied as bupropion, nortriptyline also shows promise in aiding smokers to quit.

It may not be as effective as bupropion but offers a viable alternative, particularly for individuals who may not respond to or tolerate bupropion well.

How Some Antidepressants Aid in Smoking Cessation (Mechanisms)

Neurochemical Pathways at Play

At the heart of nicotine addiction are complex neurochemical processes primarily involving dopamine, the neurotransmitter associated with pleasure and reward.

Nicotine stimulates the release of dopamine, reinforcing the smoking habit by creating a loop of craving and reward.

Antidepressants like bupropion and nortriptyline intervene in this cycle by influencing these neurotransmitter systems.

Bupropion’s Multifaceted Approach

Bupropion is unique as it acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). By blocking the reuptake of these neurotransmitters, it increases their availability in the brain.

This action not only helps alleviate withdrawal symptoms and reduce the urge to smoke but also counteracts the drop in mood often associated with quitting.

Furthermore, bupropion is a nicotinic antagonist; it blocks nicotine receptors, making smoking less satisfying and thereby reducing the urge to smoke.

Nortriptyline’s Role

Nortriptyline, a tricyclic antidepressant, works by inhibiting the reuptake of norepinephrine and serotonin, another neurotransmitter linked to mood regulation.

Its exact mechanism in smoking cessation isn’t as clear as bupropion’s, but it’s believed that its effect on these neurotransmitter systems helps alleviate withdrawal symptoms and the depressive symptoms that can accompany quitting.

Addressing Withdrawal and Reward

By mitigating the withdrawal symptoms and disrupting the nicotine reward connection, these antidepressants help smokers combat the physiological aspects of their addiction.

This support is crucial, especially in the initial stages of quitting when withdrawal symptoms are most intense and relapse is most likely.

Benefits vs. Risks of Antidepressants to Stop Smoking

Adverse Events: A Closer Look

While bupropion and nortriptyline increase the likelihood of quitting, they also come with an increased risk of adverse events.

These range from non-serious issues to serious adverse events (SAEs) including hospitalization, disability, or death.

Bupropion, in particular, has been associated with a higher dropout rate due to adverse events compared to placebo or no treatment.

Psychiatric Adverse Events

Given that many smokers have a co-occurring mental health condition, understanding the psychiatric side effects of these medications is crucial.

Both medications have been associated with an increase in psychiatric adverse events, necessitating careful monitoring and consideration, especially in vulnerable populations.

Other Antidepressants & Combinations for Smoking Cessation

The Limited Role of Other Antidepressants

While bupropion and nortriptyline stand out for their efficacy, the same cannot be said for other antidepressants like SSRIs, MAOIs, and others.

The current evidence does not support their use for smoking cessation, highlighting the unique position of bupropion and nortriptyline.

Combination Therapies

The quest for the most effective smoking cessation strategy often leads to exploring combinations of treatments.

While combining bupropion with other cessation aids like varenicline shows some promise, the evidence is still evolving, and the balance between increased efficacy and potential for added adverse events must be carefully considered.

Smoking Cessation: Specific Populations & Settings

Tailoring to Individual Needs

Not all smokers are the same, and factors like a history of depression, the severity of nicotine addiction, and individual responses to medication can influence the success of antidepressant-assisted cessation.

Further research is needed to understand how these factors interact with treatment efficacy and safety.

Adolescents and Young Adults

A small subset of studies focuses on younger populations, highlighting the need for age-appropriate cessation strategies and considerations around the use of antidepressants in these younger smokers.

Future Directions & Research Priorities

  • Expanding the Evidence Base: While current evidence provides valuable insights, there’s a need for more high-quality, long-term studies to refine our understanding of how antidepressants aid in smoking cessation, their long-term effects, and their role in different subpopulations of smokers.
  • Beyond Bupropion and Nortriptyline: As the landscape of pharmacotherapy evolves, so too should the exploration of new and existing drugs that might aid in smoking cessation. This includes not only antidepressants but also other classes of medications that might interact with the neural pathways of addiction.

Select Antidepressants May Help People Quit Smoking

The use of antidepressants, particularly bupropion and nortriptyline, offers a promising avenue for aiding smokers in their quest to quit.

However, the journey is not without its risks and complexities.

As research continues to evolve, so too will our strategies for employing these tools effectively and safely, bringing us closer to a smoke-free future.


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