Varenicline, smoking cessation and neuropsychiatric adverse events


Varenicline is a prescription drug to help people stop smoking that works by stimulating the nicotine receptors in the brain to reduce cravings and decrease the pleasure that results from smoking. Quit attempts aided by varenicline are up to 2-3 times more successful than those without (Cahill et al 2009 and 2012).

However, following the drug’s approval, concerns arose that it could be associated with an increased risk of depression and suicidal thoughts, leading the Food and Drug Administration (FDA) to issue a black box warning in 2009 (FDA, 2009). The neuropsychiatric safety of varenicline has since been debated for both the general public and patients with a history of psychiatric illness, with inconclusive results in both groups.

Gibbons & Mann (2013) have now investigated the neuropsychiatric safety of varenicline. The authors’ examined 17 random controlled trials (RCT) of varenicline, as well as retrospective data from a Department of Defence (DOD) study on the acute neuropsychiatric effects of either varenicline or nicotine replacement therapy (NRT) from a period prior to the FDA warning (2006-2007) (Meyer, 2013 and Gibbons, 2013).

Methods and Results

Randomised Controlled Trial Analysis

The authors’ reviewed 17 RCTs conducted by Pfizer totalling 4,823 participants over an average treatment duration of 11.6 weeks. 1,004 participants had a current or past psychiatric disorder. The outcomes examined were: suicidal thoughts and possible causal factors of depression aggression/agitation, as well as the unrelated side effect of nausea for a control.

There was no effect of varenicline on overall suicidal thoughts and behaviour (OR=0.57, 95% Cl 0.23 to 1.38), depression (OR=1.01, 95% Cl=0.68 to 1.52) or aggression/agitation (OR=1.27, 95% Cl 0.85 to 1.92), psychiatric illness did not moderate varenicline’s effects.

There was an effect of varenicline on nausea (OR=3.69, 95% Cl 3.03 to 4.48); however, psychiatric illness did not moderate the effect.

After 12 weeks, the probability of smoking cessation was 68% for varenicline and 30% for placebo with no evidence of an interaction of psychiatric illness, suggesting that varenicline is effective in individuals with and without a psychiatric illness (Meyer, 2013).

Observational Study: Department of Defence

Gibbons & Mann (2013) compared data from the military health system to measure acute adverse events. 19,933 patients were treated with varenicline while 15,867 were given NRT, with data also including patients with a past or present psychiatric illness (Meyer, 2013).

After adjusting for possible confounding factors, the risks of neuropsychiatric events were lower for varenicline (2.28%) than NRT (3.16%).

Of the nine outcomes examined, only transient mental disorder was observed more frequently in varenicline, however even this was a low number of observations (9 cases) resulting in very low power (0.05% of people given varenicline) compared to the 4 cases seen in NRT (0.03% of people treated with NRT) (Gibbons, 2013) thus conclusions are hard to draw from it.

The review found

The review found no significant effect of varenicline on neuropsychiatric adverse events


This review of the literature has shown that the use of varenicline to aid in smoking cessation poses no increased risk of suicidal tendencies or other neuropsychiatric adverse events either during or after its use.  Additionally, as it included a large percentage of individuals with a past or present psychiatric illness in the analysis, this suggests there was no evidence that this population would be affected by adverse neuropsychiatric events when using varenicline. Nausea was the only main adverse effect found for patents using varenicline, and this generally decreased over time.

In terms of efficiency, after 12 weeks of treatment, varenicline was 124% more effective compared to the placebo, and 22% more effective compared to bupropion. Gibbons & Mann (2013) conclude:

There is little evidence from controlled studies of any link between varenicline and psychiatric adverse effects.

However, It’s important to note that Pfizer, the pharmaceutical company that markets varenicline, conducted all the RCTs investigated in the study. Pfizer also provided the data for the RCTs and reviewed the final manuscript.  Additionally, one of the authors has previously served as an expert witness in a case involving Pfizer and neuropsychiatric adverse events. Future reviews should include a more varied sample of studies to reduce any possible bias.

Fellow woodland friend and blogger, Andrew Jones, is preparing a blog on increased aggression and depression from cessation drugs which recently appeared in the British Medical Journal (Thomas, 2013). The authors use a clinical practice database to gather information on possible adverse events from individuals’ prescribed different cessation drugs. Results indicated no increased risk of suicide, non-fatal self-harm, or depression. Andrew’s blog will take a closer look at the Thomas (2013) review, and will appear on January 13th.

If you are interested in stopping smoking visit or call smokefree: 0800 022 4 3322

This review concludes that varenicline is a safe and effective treatment for smoking cessation, with no reported neuropsychiatric adverse events of note

This review concludes that varenicline is a safe and effective treatment for smoking cessation, with no reported neuropsychiatric adverse events of note


Gibbons R, Mann J: Varenicline, smoking cessation, and neuropsychiatric adverse events. American Journal of Psychiatry. 2013: 170: 1460-1467. [PubMed abstract]

Meyer TE, Taylor LG, Xie S, Graham DJ, Mosholder AD, Williams JR, Moeny D, Quellet-Hellstrom RP, Coster TS: Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System. Addiction 2013; 108:203–210 [PubMed abstract]

Cahill K, Stead L, Lancaster T: A preliminary benefit-risk assessment of varenicline in smoking cessation. Drug Saf 2009;32:119–135 [PubMed abstract]

Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2012; 4:CD006103 [PubMed abstract]

US Food and Drug Administration (FDA) black box warning: Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Silver Spring, Md, FDA, July 1, 2009.

Thomas, KH, Martin, RM, Davies, NM, Metcalfe, C, Windmeijer, F & Gunnell, D (2013). Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort studyBMJ, vol 347., pp. f5704

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