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Current Year Centre for Addiction
and Mental Health

Nicotine gives brain more pain relief from codeine, changing our view of the brain’s role in metabolizing drugs

TORONTO, October 15, 2015 — According to new research, nicotine use over time increases the speed that codeine is converted into morphine within the brain, by increasing the amount of a specific enzyme. It appears smokers’ brains are being primed for a bigger buzz from this common pain killer – which could put them at a higher risk for addiction, and possibly even overdose.

“We’ve known for some time that codeine was metabolized in the liver, but we’ve now discovered that this is also happening within the brain itself,” Dr. Rachel Tyndale, senior scientist in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH), and University of Toronto pharmacology, toxicology, and psychiatry professor.

Brain image
“Chronic nicotine use, or smoking, increases the amount of an enzyme that converts codeine into morphine within the brain, increasing pain relief. This may also make you more prone to addiction as the faster a drug gives you a high, the easier it is for you to learn the behavior and become addicted.”

These findings, published earlier this year in the peer-reviewed journal Neuropsychopharmacology, contribute to a new way of seeing the brain’s role when it comes to drugs and toxins. Instead of a passive target with receptors idly waiting for drugs, Dr. Tyndale has found that the brain is actually playing a much more active role than was previously thought. Enzymes in the brain are busy breaking down – or ramping up – the effect of drugs and other substances. Understanding these enzymes – and our genetic variation affecting our brain’s metabolism – could help explain why people react differently to drugs and toxins, and even why certain people are more susceptible to complex diseases like Parkinson’s disease.

“This is opening up a whole new area of research and potentially a substantial source of variation between people in their response to drugs and toxins acting on the brain,” says Dr. Tyndale. “We’re starting to see patterns and relationships, like the nicotine and codeine connection. This is also of interest in drug development as we might be able to create drugs that are only activated once they get to the brain.” 

For this study, Tyndale, and her graduate student Douglas McMillian tested differences in response to pain relief in four preclinical models. The group that received nicotine for seven days, followed by codeine, had substantially more morphine and greater pain relief than other groups.  However, the levels of morphine in the blood remained around the same for all groups.

The implications are that people with more of this enzyme in their brain, whether due to genetic factors, smoking, vaping or other nicotine use, might be getting more pain relief but could be at greater risk of codeine dependence.

“This work could explain a lot of the mysteries when it comes to why people react so differently to different drugs, even when their blood levels seem to be similar,” says Dr. Julia Stingl, a professor of translational pharmacology at the University of Bonn Medical School and a clinical pharmacologist who treats patients with depression and additions. “Understanding the effects of smoking on metabolizing enzymes in the brain could have an extreme impact on clinical practice.”

Variation in how people react to drugs has long puzzled clinicians and researchers. For example, certain people do not have any of the enzyme that converts codeine into morphine. For a time health care workers believed these individuals were abusing their medication – continually asking for more – when in fact they were not getting any pain relief.

Dr. Tyndale’s research into how the brain metabolizes drugs and toxins could expand our understanding of a host of unexplained associations. For example, researchers have found that smokers have a lower risk of developing Parkinson’s disease compared to their non-smoking counterparts. Dr. Tyndale has found that the same enzyme that converts codeine into morphine – the one increased with nicotine intake – is also able to break down a toxin that causes a Parkinsonian symptom in animal models. She’s currently doing more research into this link.

Viewing the brain not just as a passive array of receptors for drugs, but as an active metabolizer, stands to reveal important insights into how we react differently to a range of medications, drugs, toxins and even our susceptibility to certain diseases. Dr. Tyndale is currently expanding her research into variation in human brain enzyme activity, using a variety of experimental and imaging approaches.


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The Centre for Addiction and Mental Health (CAMH) is Canada’s largest mental health and addiction teaching hospital and a world leading research centre in this field. CAMH combines clinical care, research, education, policy development and health promotion to help transform the lives of people affected by mental illness and addiction. CAMH is fully affiliated with the University of Toronto, home to the Campbell Family Mental Health Research Institute and is a Pan American Health Organization/World Health Organization Collaborating Centre. For more information, please visit or follow @CAMHnews on Twitter.

Media Contact:

Kate Richards
Media Relations
Centre for Addiction and Mental Health (CAMH)
(416) 595-6015

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