Uncovering what makes or breaks an addiction
From the first time someone smokes a cigarette, what makes one person likely to eventually become a chronic smoker and another not? And why is quitting smoking harder for some people than for others?
These questions are driving research by CAMH’s Dr. Rachel Tyndale, Senior Scientist and Head of the Pharmacogenetics Lab in the Campbell Family Mental Health Research Institute.
Her research is tackling addiction from two sides: what leads to dependence and what affects treatment response. Dr. Tyndale is building strong evidence that the path to smoking addiction involves how our body breaks down nicotine. Our unique genetic makeup affects this biological process to make us more or less at risk of dependence, and more or less likely to respond positively to different types of smoking cessation treatments.
“A very hard target”
"We're working with a very hard target – breaking addictions," says Dr. Tyndale, who is also the Endowed Chair in Addictions and Professor in the Departments of Psychiatry, Pharmacology and Toxicology at the University of Toronto. According to the most recent CAMH Monitor survey, nearly 17 per cent of Ontario adults – representing an estimated 1.7 million people – reported smoking, and, on average, smoked 11 cigarettes a day.
Understanding the risk factors leading to success or failure of treatments is key because “we don't get that many shots at helping someone quit their addiction," she says. While 40 per cent of smokers try to quit each year, only three per cent succeed, and smokers who relapse may not try to quit again for a long period, if ever.
“One goal of my research is to develop new treatments and optimize current treatments to help people quit smoking,” says Dr. Tyndale.
A major early discovery in her research was pinpointing the enzyme – called CYP2A6 – that is responsible for breaking down nicotine in the liver. She also found that this enzyme differs among people, based on the gene that encodes the enzyme or enables it to work. In some people, their genetic makeup means that this enzyme breaks down nicotine at a “normal” rate, while other people have impaired or slower nicotine metabolism.
To tease out how and why people differ, Dr. Tyndale’s research spans the full spectrum of smoking behaviours, from the earliest onset in the teen and young adult years, to people seeking treatment to quit. She uses different approaches, including community studies, large-scale clinical trials, longitudinal studies, brain imaging and preclinical models, and her work is “hugely collaborative” with researchers in Canada and internationally, she says.
Over multiple studies, Dr. Tyndale has shown that the rate at which a person breaks down nicotine has a major effect on smoking behaviours, from the age when a person starts smoking, to the number of cigarettes smoked a day and the ability to stop smoking.
Having slower nicotine metabolism offers protection against several risk factors related to smoking (see below, “Slower metabolism, greater protection”).
The nicotine metabolism rate also determines how people respond to treatment when they’re trying to quit smoking. In a first-of-its-kind, multi-site prospectively randomized clinical trial, Dr. Tyndale and collaborators showed that people who are slow metabolizers are better off being prescribed a nicotine patch, while normal metabolizers are more likely to quit if they take a prescription of varenicline (sold as Champix in Canada).
These research findings are getting closer to practical use. Dr. Tyndale is working with a company funded by the National Institute on Drug Abuse (NIDA) in the U.S. to create and evaluate the effectiveness of a commercial kit that will identify a person’s rate of nicotine metabolism. The personalized test results will guide health care professionals in choosing the most effective medication to help a patient quit smoking. Dr. Tyndale is also working towards being able to use genetics alone to estimate the rate of nicotine metabolism in different people, anticipating that within a year or two this may be possible. This could lead to a genetic test that predicts a person’s rate of nicotine metabolism.
The brain’s piece of the puzzle
Understanding the brain’s unique role in drug metabolism is another key area of Dr. Tyndale’s research.
While the liver is the main organ that breaks down all drugs in our bodies, her research is showing that the brain can play an active and unique role in altering drug concentrations and drug response. A study published in 2015 revealed that metabolism of codeine occurred in the brain, in addition to the liver. As well, chronic smoking increased the amount of an enzyme in the brain – called CYP2D – that breaks down codeine. “We’re interested in how these brain enzymes matter differently from liver enzymes,” says Dr. Tyndale, a question driving ongoing research.
In other new directions, Dr. Tyndale is pursuing multiple areas, including e-cigarette smoking and other CYP enzymes. She is also investigating the role of genetic variation in drug metabolism related to other drugs of abuse, including opiates and amphetamines.