Many people who smoke still do not receive comprehensive cessation treatment. In 2022, only about half of U.S. adults who smoked and had seen a health professional reported receiving advice or assistance to quit, and only 38.3% of people who made a quit attempt or recently quit used counseling or medication.¹ Behavioral counseling and FDA-approved medications are generally most effective when used together.^1,2 We provide structured cessation support and discuss the two established non-nicotine prescription options, varenicline and sustained-release bupropion, as well as nicotine-replacement strategies when appropriate.²

Varenicline

Varenicline is a partial agonist at α4β2 neuronal nicotinic acetylcholine receptors. It provides lower-level receptor stimulation that can reduce cravings and withdrawal while also limiting nicotine’s ability to activate the same receptors and reinforce smoking.³

Among approved single-medication options, varenicline has the strongest efficacy evidence. It more than doubles long-term smoking-cessation rates compared with placebo and is more effective than bupropion or a single form of nicotine-replacement therapy.^2,4 It is commonly started 1 week before the target quit date and continued for 12 weeks. An additional 12 weeks may be recommended for people who have quit successfully, and alternative start or quit-date schedules may be individualized.³

In 2021, Pfizer recalled all U.S. lots of brand-name Chantix because levels of the nitrosamine impurity N-nitroso-varenicline met or exceeded the FDA’s interim acceptable intake limit.⁵ The FDA also approved the first generic varenicline product in 2021, and varenicline remains an approved prescription option.^3,6

Earlier concerns about depression, suicidal ideation, and other neuropsychiatric effects are now understood more precisely. In the EAGLES trial, varenicline did not significantly increase moderate or severe neuropsychiatric adverse events compared with nicotine patch or placebo in participants with or without psychiatric disorders. The American Thoracic Society also recommends varenicline over a nicotine patch for adults with comorbid psychiatric conditions.^2,7 Serious mood or behavior changes have nevertheless been reported after marketing, so patients should be monitored and should contact a clinician promptly for agitation, depressed mood, suicidal thoughts, or marked changes in behavior or thinking.³ Common adverse effects include nausea, which is often mild to moderate and temporary, and abnormal or vivid dreams.³

Bupropion SR (Zyban)

Bupropion SR is a non-nicotine medication. Its exact smoking-cessation mechanism is not fully established, but it is thought to work through noradrenergic and dopaminergic pathways and weakly inhibits neuronal reuptake of norepinephrine and dopamine.⁸ High-certainty evidence shows that bupropion increases long-term smoking cessation by approximately 60% compared with placebo or no medication.⁹ It is generally started about 1 week before the planned quit date and continued for 7 to 12 weeks, with longer treatment considered for selected patients.⁸

Bupropion may be considered when a patient prefers it, cannot tolerate varenicline, or has another clinical reason to select it.^2,8 Bupropion is also the active ingredient in Wellbutrin antidepressant products, but the formulations and approved indications differ. Zyban is not itself indicated for the treatment of depression, so coexisting depression and smoking cessation should be evaluated as related but distinct treatment decisions.⁸ Bupropion may modestly reduce weight gain during active treatment, but a durable weight-prevention benefit at 12 months has not been established.¹⁰

Bupropion is contraindicated in patients with a seizure disorder or a current or prior diagnosis of bulimia or anorexia nervosa. Additional contraindications include certain abrupt alcohol or sedative withdrawal states and use of monoamine oxidase inhibitors within specified time periods, so a complete medical and medication history is essential before treatment.⁸

Combination Therapy

Combination treatment can be considered after an individualized review when nicotine dependence is high or a single-medication approach has been insufficient.² The American Thoracic Society conditionally suggests varenicline plus a nicotine patch over varenicline alone, but the supporting evidence is considered low certainty. A later randomized clinical trial found no significant 52-week cessation benefit from adding a nicotine patch to varenicline.^2,11 Bupropion plus nicotine-replacement therapy may also be prescribed, although current evidence does not establish a clear incremental quit-rate benefit over nicotine-replacement therapy alone. Blood pressure should be monitored because the combination can increase the risk of treatment-emergent hypertension.^8,9

Clinical note: Medication selection and dosing should be individualized based on pregnancy status, kidney function, seizure risk, psychiatric history, blood pressure, drug interactions, and other clinical factors. This content is educational and does not replace an individualized medical evaluation.^2,3,8

References

1. VanFrank B, Malarcher A, Cornelius ME, et al. Adult smoking cessation: United States, 2022. MMWR Morb Mortal Wkly Rep. 2024;73(29):633-641. doi:10.15585/mmwr.mm7329a1.
2. Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-dependent adults: an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;202(2):e5-e31. doi:10.1164/rccm.202005-1982ST.
3. Pfizer Inc. CHANTIX (varenicline) tablets: prescribing information. Revised June 2025. US Food and Drug Administration. Accessed June 20, 2026. FDA prescribing information.
4. Livingstone-Banks J, Fanshawe TR, Thomas KH, et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2023;(6):CD006103. doi:10.1002/14651858.CD006103.pub9.
5. Pfizer Inc. Pfizer expands voluntary nationwide recall to include all lots of Chantix (varenicline) tablets due to N-nitroso-varenicline content. US Food and Drug Administration. Published September 16, 2021. Accessed June 20, 2026. FDA recall notice.
6. US Food and Drug Administration. 2021 first generic drug approvals. Updated February 10, 2022. Accessed June 20, 2026. FDA generic-drug approval list.
7. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders: a double-blind, randomized, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. doi:10.1016/S0140-6736(16)30272-0.
8. GlaxoSmithKline. ZYBAN (bupropion hydrochloride) sustained-release tablets: prescribing information. Revised March 2021. US Food and Drug Administration. Accessed June 20, 2026. FDA prescribing information.
9. Hajizadeh A, Howes S, Theodoulou A, et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2023;5(5):CD000031. doi:10.1002/14651858.CD000031.pub6.
10. Hartmann-Boyce J, Theodoulou A, Farley A, et al. Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev. 2021;10(10):CD006219. doi:10.1002/14651858.CD006219.pub4.
11. Baker TB, Piper ME, Smith SS, et al. Effects of combined varenicline with nicotine patch and of extended treatment duration on smoking cessation: a randomized clinical trial. JAMA. 2021;326(15):1485-1493. doi:10.1001/jama.2021.15333.