Grant: Foundation Grant

Smoking kills a Canadian every 15 minutes, yet rates have stabilized at 13%. Prescription opioid (PO) related harm now ranks 3rd for substance abuse. Prevention and treatment of these dependencies require new evidence-based responses. Our overarching goal is to determine how variation in liver and brain drug metabolism impacts on tobacco and prescription opioid dependence, changes to the brain and to treatment response. We focus on three highly genetically variable enzymes that metabolize these drugs of abuse and their treatment drugs: CYP2A6, CYP2B6 and CYP2D6. Program 1A. Genetic variation in nicotine inactivation alters smoking cessation and response to reduced-nicotine cigarettes. Tests among PO addicts how this variation impacts smoking, PO intake and changes in the brain. Program 1B. Tests how CYP2B6 and CYP2D6 pharmacogenetics alters PO treatment efficacy in a clinical trial of methadone vs buprenorphine/naloxone. Program 1C. Variation in nicotine inactivation alters the brain. Tests how this variation alters: 1) smoking-induced neurological changes in adolescent smokers; 2) response to nicotine dose; 3) response to treatment drugs, and how long it takes to recover following cessation. Program 2A. Codeine is activated by CYP2D6 to morphine; higher brain CYP2D increases pain relief, while inhibition reverses it. We will use animal models to investigate variable brain CYP2D effects on codeine/morphine levels, integrated with drug response and reward. Program 2B. Tests the neuroprotective impact of brain CYP2D on drugs and toxins to model the influence of smoking on Parkinson's Disease, Essential Tremor, and Tardive Dyskinesia. Impact and Significance. Variation in rates of drug metabolism substantially alters individual response to drugs of abuse and their treatments. Our improved understanding of this variation will lead to better prevention and harm reduction strategies and optimized treatment.