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Nortriptyline, moclobemide and clonidine have been found in smoking cessation trials in healthy smokers to be safe in doses approved for the treatment of depression/hypertension.

The anti-depressants nortriptyline and moclobemide and the central alpha adrenergic agonist clonidine have been reported in clinical trials to aid smoking cessation (Hughes et al., 2007; Hughes et al., 2005; Berlin et al., 1995; Gourlay et al., 2004; Fiore et al., 2008). These drugs have not been approved by regulatory authorities for smoking cessation, but are used by some prescribers.

Nortriptyline is a tricyclic anti-depressant drug, which when used in doses of >150 mg/day to treat depression commonly causes dry mouth and sometimes lightheadedness, blurred vision, constipation and urinary retention. In overdose nortriptyline has severe, and potentially fatal, cardiovascular and brain toxicities. In smoking cessation trials, the typical dose used is 75-150 mg and at this dose, the rate of discontinuation due to adverse events is similar to that with bupropion and varenicline (i.e. <10%) and serious adverse event are very rare. 

Moclobemide is a reversible monoamine oxidase A inhibitor anti-depressant which in overdose may be associated with life-threatening toxicity. In addition, the consumption of some foods or drugs along with moclobemide can cause severe side effects. In clinical trials of smoking cessation, when taken in doses similar to those used to treat depression, the major side-effect was insomnia.  The rate of discontinuation due to adverse events was small and no serious adverse events have been found.

Clonidine is a central alpha adrenergic agonist that has been used mostly as an anti-hypertensive.  When used as either a patch or pill at doses of 0.1 to 0.45 mg/day, the major side effects are postural hypotension, dry mouth, sedation and dizziness.  In addition, abruptly stopping clonidine can cause rebound withdrawal and hypertension.  Discontinuations due to adverse events occurred in about 10% of participants and serious adverse events were very rare. 

These three medications have had fewer adverse events when used to treat smoking than when used to treat depression or hypertension, probably due to the use of lower doses when treating smoking and use in generally healthy subjects. Even so, the existing data suggest their risk profile appears to be somewhat worse than NRT, bupropion and varenicline; however, the number of persons exposed in these trials is too small to draw any definitive conclusions.

Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2007; 1.

Hughes JR, Stead LF, Lancaster T. Nortriptyline for smoking cessation: a review. Nicotine Tob Res. 2005; 7: 491-499.

Berlin I, Saïd S, Spreux-Varoquaux O, Launay JM, Olivares R, Millet V, Lecrubier Y, Puech AJ. A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin Pharmacol Ther. 1995; 58: 444-452.

Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev, 2004; (3): CD000058.

Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. logo
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