The smoking cessation aids varenicline (Chantix) and bupropion (Zyban) do not show a significant increase in neuropsychiatric adverse events compared to the nicotine patch and a placebo, according to data published in The Lancet.

After reports claiming varenicline and bupropion might cause adverse neuropsychiatric events, such as increased agitation, depression, hostility or suicidal behavior, the
Food and Drug Administration (FDA) requested that both medications carry boxed warnings in their labeling, which resulted in limitation in use and thus fewer ways to quit.

There are 1 billion smokers in the world and nearly 6 million deaths blamed on smoking each year, but there are only three approved medication treatments for quitting: nicotine replacement therapies like the patch and the two non-nicotine medications, bupropion and varenicline.

None of them work all that well, smokers have to really struggle to quit, and thus fewer options are no good for anyone. To find out if the effects were real or just epidemiological or self-reported exaggeration, Pfizer and GlaxoSmithKline, makers of varenicline and bupropion, respectively, got together with the FDA to design and fund the EAGLES study to get some answers. Critics of modern science and health will see corporate names and insist the studies are flawed, but such studies must be corporate-funded by law. If any product could be placed on the market or kept there with the insistence only government scientists could study them, the waiting list would be 100 years and counting. 

Robert Anthenelli, MD, professor of psychiatry, director of the Pacific Treatment and Research Center at UC San Diego School of Medicine and first author of the study, said the EAGLES study is important because it prospectively examined the neuropsychiatric safety risks and quit-enhancing potential of the three medication classes versus placebo in a rigorous, adequately-sized, randomized controlled trial: more than 8,000 smokers seeking to quit in 16 countries over a period from November 2011 to January 2015. Trial participants, investigators and research personnel were blinded to who received which treatment.

"This is the first study to compare the safety and efficacy of the three first-line smoking cessation aids on the market, head-to-head, in smokers. It's the largest double-blind smoking cessation medication trial to date," said Anthenelli. "And no study has done so in smokers with current or past psychiatric disorders who consume roughly 45 percent of the cigarettes sold in the U.S."

In terms of safety, approximately 2 percent of non-psychiatric participants reported moderate or severe adverse neuropsychiatric events for any of the treatments. Specifically, 1.3 percent for varenicline, 2.2 percent for bupropion, 2.5 percent for the nicotine patch and 2.4 percent for placebo.

In the cohort of participants with psychiatric disorders, moderate and severe adverse neuropsychiatric events were slightly higher across the board: 6.5 percent for varenicline, 6.7 percent for bupropion, 5.3 percent for the nicotine patch and 4.9 percent for placebo.

Anthenelli said the risk difference in the incidence of serious neuropsychiatric adverse events for varenicline and bupropion was not significantly higher than placebo - but that psychiatric patients trying to stop smoking are likely to have more confounding factors in treatment and appear to have a harder time quitting.

The efficacy or success rate, measured as biochemically-confirmed continuous abstinence for weeks nine to 12 after treatment began, was broadly consistent with past research and predictions. Regardless of participants' psychiatric status, varenicline was found to be more effective at helping smokers achieve abstinence than bupropion, the patch or placebo; bupropion and patch were more effective than the placebo. Across all cohorts, the most frequent adverse events were nausea, insomnia, abnormal dreams and headache.