Smokers’ metabolism of nicotine could point to the best way to quit

A study finds normal metabolisers have greater success with varenicline than nicotine patches when giving up smoking.

Discovering how quickly a smoker metabolises nicotine could help identify the most effective method of smoking cessation, study finds

The speed at which smokers metabolise nicotine may suggest the most effective smoking cessation method — either varenicline (Champix, manufactured by Pfizer) or the nicotine patch, according to a study published in The Lancet Respiratory Medicine
on 11 January 2015.

Scientists have known for nearly two decades that genetic variants — the kind that influence the levels of dopamine, serotonin and other brain chemicals — play a role in both the development of nicotine dependence and in the ability to quit smoking. A breakthrough occurred about ten years ago, when scientists noted variants in a gene known as CYP2A6, which encodes an enzyme that metabolises nicotine in the liver.

“Genetic variants of CYP2A6 can decrease or inactivate the enzyme, an action that can turn smokers into slow metabolisers of nicotine,” says Robert A Schnoll, co-author of the study and associate professor of psychiatry at the University of Pennsylvania School of Medicine.

Normal or faster metabolisers of nicotine retain nicotine for shorter periods than slow metabolisers. This, explains Schnoll, makes them more nicotine-dependent and subject to cravings, more likely to smoke a greater number of cigarettes daily, more prone to severe withdrawal symptoms, and more reactive to environmental cues tied to smoking.

The randomised clinical trial, conducted at the University of Pennsylvania and three other sites, aimed to find out whether varenicline or the nicotine patch worked more effectively as a smoking-cessation aid, depending on a smoker’s rate of nicotine metabolism. The study involved 1,246 treatment-seeking smokers, whose blood was tested to assess the ratio of two metabolites derived from nicotine — 3’hydroxycotine and cotine — with that ratio reflecting CYP2A6 activity. Of the participants, 662 were categorised as slow metabolisers, with the remaining 584 identified as normal metabolisers.

Over a period of 11 weeks, the participants — who all received behavioural counselling — were randomised to receive either the nicotine patch (plus a placebo pill), varenicline (plus placebo patch), or a placebo pill and patch. After the treatment stopped, researchers followed up with participants at six months and twelve months.

At the end of treatment, varenicline was more effective than the nicotine patch in normal metabolisers — nearly 40% of normal metabolisers taking varenicline were still abstaining from smoking at the end of treatment compared with 22% who used the active patch (odds ratio 2.17, 95% confidence interval 1.38–3.42; P=0·001) — but not in slow metabolisers (odds ratio 1.13, CI 0.74–1.71; P=0·56).

Although the efficacy was equivalent for slow metabolisers, this group reported more overall side effects, which suggested more benefit would be gained by using the patch. The quit rates decreased at the six-month and twelve-month mark, but the ratios for both normal and slow metabolisers using the patch and varenicline remained.

Schnoll hopes that, within the next decade, pharmacies will be able to offer a point-of-care test to help smokers understand their nicotine-metabolism rate.

Meanwhile, he suggests that pharmacists can help smokers understand their previous lack of success with nicotine patches. Pharmacists who explain the science of nicotine metabolism to consumers eager to become ex-smokers may be providing a vital piece of encouragement to not give up on their attempts to quit, he says.

The study was funded by the US National Institutes of Health, the Canadian Institutes of Health Research, the Abramson Cancer Center, the Centre for Addiction and Mental Health Foundation and the Pennsylvania Department of Health.


[1] Lerman C, Schnoll RA, Hawk LW et al. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. The Lancet Respiratory Medicine 2015. doi:

Last updated
The Pharmaceutical Journal, PJ, 24 January 2015, Vol 294, No 7846;294(7846):DOI:10.1211/PJ.2015.20067565

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