Current and emerging pharmacotherapies for treating tobacco dependence.

Tobacco dependence remains the leading cause of death and disease in the US and a major cause of mortality around the world, yet 1 out of 5 American adults smoke and 1.3 billion adults smoke worldwide. Nicotine replacement therapies (NRTs), bupropion and varenicline, are approved by the US FDA as first-line treatments for nicotine dependence. Clonidine and nortriptyline are recommended as second-line treatments by the Agency for Healthcare Research and Quality. Although recent data suggest that varenicline is superior to bupropion for treating nicotine dependence, a majority of smokers fail to maintain long-term abstinence from smoking using FDA-approved pharmacotherapies. Thus, continued investigation of novel medications for nicotine dependence remains a critical priority. Guided by research on multiple neurobiological mechanisms of nicotine dependence, several novel medications that mimic and/or attenuate nicotine's rewarding effects, or reduce nicotine withdrawal, are under investigation. Although existing data are limited or conflicting, there is some evidence for the efficacy of selegiline, fluoxetine, naltrexone and mecamylamine in certain subgroups of smokers. New research directions, such as fast-acting NRTs, the tailored use of NRTs for subtypes of smokers, and pharmacogenetics, hold promise for new treatment approaches and, ultimately, for reducing rates of tobacco use in the US and worldwide.