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| Publication Abstract Display | | Type: Published Abstract | | Title: Putative cytochrome P450-2D6 metabolic activity and cognitive functioning in methamphetamine dependence. | | Authors: Cherner M, Bousman C, Letendre S, Vaida F, Heaton R, Atkinson JH, Grant I, and the TMARC Group | | Year: 2010 | | Publication: Translational Research in Methamphetamine Addiction Conference, July 19-21, Pray, Montana | | Volume: Issue: Pages: | | Abstract:BACKGROUND: Heavy exposure to methamphetamine has been linked to neurocognitive deficits. However, methamphetamine use parameters such as length of abstinence, lifetime consumption, chronicity, mode of delivery, etc., are often unrelated to degree of cognitive and motor dysfunction, suggesting the possibility of individual differences in vulnerability to methamphetamine-associated neurotoxicty. We hypothesized that some of these differences may be explained by variability in metabolic clearance of methamphetamine. Cytochrome P450-2D6 (CYP2D6) is highly a polymorphic enzyme responsible for oxidative metabolism of methamphetamine. CYP2D6 metabolic phenotypes include extensive, intermediate, poor, and more rarely ultrarapid metabolizers, according to the level of activity conferred by each of two alleles. We examined the relationship between cognitive functioning and putative metabolic activity associated with known CYP2D6 polymorphisms.
PARTICIPANTS AND METHOD: Participants were 39 men and 13 women from the San Diego, CA region with a history of DSM-IV diagnosed methamphetamine dependence. The sample was 77% non-Hispanic white, 10% Hispanic, and 3% other, with a mean age of 39 (SD=10) years and an average of 12.6 (1.9) years of education. All were HIV and hepatitis C negative. They received a neuropsychological test battery as well as structured interviews to ascertain degree of exposure to methamphetamine and other substances. CYP2D6 genotype was obtained from blood-derived DNA. Participants’ estimated CYP2D6 activity was rank-ordered from 1 (lowest) to 5 (highest) based on the combination of active, partially active, or inactive alleles present in their genotype, guided by published data. Global and domain-specific neuropsychological deficit scores were computed from demographically adjusted test scores. We explored linear and quadratic relationships between putative metabolic activity and neuropsychological deficit scores.
RESULTS: Phenotypes included 33 extensive, 17 intermediate, and 3 poor metabolizers. Significant correlations emerged between greater CYP2D6 activity and worse neuropsychological performance globally (ρ=0.35, p<.02) and in the learning (ρ=0.37, p<.007), processing speed (ρ=0.33, p<.017), and abstraction (ρ=0.33, p<.018) domains. The 3 cases with lowest activity also tended to have worse performance, suggesting a nonlinear relationship. Quadratic fits to the data were significant for learning (p<.001), delayed recall (p<.003), and verbal fluency (p<.032), with a trend for global performance (p<.086). Extent and recency of prior methamphetamine use were not associated with neuropsychological performance. |
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