Research Profile - The origins of addiction
Dr. Rachel Tyndale
Nicotine-metabolizing enzymes appear to play a key role in which smoking cessation treatment works best for which smoker.
Why are some smokers content to light up a few cigarettes a day, while others need a pack or more to get through 24 hours? And why can some people overcome nicotine addiction relatively easily, while others find life without tobacco virtually impossible?
According to Dr. Rachel Tyndale at the University of Toronto, the unfortunate truth is that the better a person is at metabolically inactivating nicotine, the more they need cigarettes and the harder it will be for them to quit the life-shortening, cancer-causing dependence.
"An enzyme expressed in the liver called CYP2A6 is involved in the metabolic inactivation of nicotine," says Dr. Tyndale. "There is a wide range of activity for this enzyme: from having no active copies at all, right up to those who have inherited multiple copies of the gene."
At a Glance
Who – Dr. Rachel Tyndale, Professor, University of Toronto, Head of Pharmacogenetics, Centre for Addiction and Mental Health, Canada Research Chair.
Issue – Genetic biomarkers, such as the presence and activity of a liver enzyme called CYP2A6, indicate some smokers metabolize nicotine faster, have stronger cravings for cigarettes and are at greater risk for long-term tobacco addiction.
Approach – Dr. Tyndale leads a four-year study comparing biological data gathered from an ongoing cohort study of 1,200 Canadians from adolescence through adulthood, and Finnish studies with several thousand participants to test genetic biomarkers that make people vulnerable to addiction.
Impact – The knowledge gained will lead to better-targeted approaches to prevent addiction, and advance the development of more personalized smoking-cessation treatments.
Smokers who have high CYP2A6 enzymatic activity neutralize nicotine quickly, creating cravings for more cigarettes to avoid tobacco withdrawal.
Dr. Tyndale leads a four-year, CIHR-funded project to investigate the origins of addiction among adolescents. She will be comparing biological data gathered by Dr. Jennifer O'Loughlin of the University of Montreal with data from Finnish studies led by Dr. Jaakko Kaprio. In doing so, Dr. Tyndale hopes to improve understanding of the biological mechanisms that stack the odds of becoming - and staying - addicted.
"Because addiction occurs principally in adolescence, a lot of our focus is there," says Dr. Tyndale. "We're looking at the timeframe between when people first become smokers to when they stop smoking, following that up in the O'Loughlin cohort, which has tracked 1,200 participants through adolescence and is in the midst of doing the measurements at age 25."
Dr. Tyndale will compare the Canadian findings against results from the Finnish studies, which have looked at thousands of individuals for several decades. "We want to look at the robustness of some genetic and biomarker signals within the Finnish cohorts and examine these in the Canadian cohort. That gives us a handle on how strong a genetic signal is and if it's strong across different environments."
Ultimately, her research is aimed at enabling a more personalized approach to treating addiction. And that is where genetic factors come into play.
"For example, we know from our previous studies that the nicotine patch works extremely well in slow metabolizers - partly because the pattern of nicotine kinetics - that slow metabolism of nicotine - is mimicked by the patch. We have large clinical trials going on right now in adults."
But the patch may not be the preferred approach for fast metabolizers, whose rapid rate of nicotine "inactivation" isn't in sync with the cessation treatment's slow release of the drug.
"We've been looking at bupropion (an antidepressant marketed under the trade name Zyban) and it seems to work quite effectively in the fast metabolizers. So that's one possibility. Also, we've got some pilot data and now we're running a clinical trial that would suggest that varenicline (marketed in Canada as Champix) is also effective in fast metabolizers and may be a good approach for them."
The point, she says, is to even the odds for those who have a genetic vulnerability to tobacco addiction. "The hope is that by understanding the effects of biology and environment, we can understand who is at greater risk and why. We can use that knowledge to develop better prevention tools or design better medications for treatment."
If we can interrupt that smoking pattern or that ongoing escalation in smoking earlier in a person's smoking history, we have a much better chance of helping them to stop. Otherwise, you're often looking at 25 or 30 years of smoking before people really quit.
- Dr. Rachel Tyndale, University of Toronto