In May 2006, the FDA approved varenicline as an aid for smoking cessation. In a meta-analysis of four trials, varenicline was found to significantly improve quit rates compared to placebo.

In some patients, use of varenicline has been associated with seizures, enhanced effects of alcohol, accidental injury, cardiovascular events, angioedema, hypersensitivity reactions, and serious skin reactions. These are rare events, and most have not been causally linked to varenicline use.

In July 2009, the FDA mandated that the prescribing information for varenicline include a black-boxed warning highlighting the risk of serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. However, some of these symptoms have occurred in patients taking varenicline who continued to smoke.

Clinicians should be aware that patients with serious psychiatric illness (e.g., depression, schizophrenia, bipolar disorder) did not participate in the pre-marketing studies of varenicline and the safety and efficacy of varenicline in such patients has not been established.