CYP2D6 genotype may moderate measures of brain structure in methamphetamine users

Abstract

Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine‐dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM‐IV] criteria) and 79 healthy‐control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine‐dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (β = −0.254; p = 0.035), but not in control subjects (β = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine‐induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.

Sex Differences in Substance Use Disorders: A Neurobiological Perspective

“…General neuroimaging results following methamphetamine use disorder (MUD) have recently been reviewed (32) and extended (33)(34)(35)(36), consistently reporting alterations to corticostriatal regions. Notably there are structural and/or functional changes to insula, inferior and precentral gyrus, striatum, and frontal cortex.…”

Cortical thickness and related depressive symptoms in early abstinence from chronic methamphetamine use

“…Some of these data were used in other analyses. 20,[29][30][31][32][33][34][35][36] Participants were recruited with online and print advertisements. They provided written informed consent after a detailed explanation of the respective studies and received monetary compensation.…”

“…This cross‐sectional investigation pooled data from studies were approved by the institutional review board of the University of California at Los Angeles. Some of these data were used in other analyses 20,29–36 . Participants were recruited with online and print advertisements.…”

Age Influences Loss Aversion Through Effects on Posterior Cingulate Cortical Thickness

“…130 participants (40 women) completed the Loss Aversion Task and 24 were excluded during analysis of the behavioral data (see procedures for exclusion under Loss Aversion Task below), leaving 106 for final analysis. MRI and behavioral data from these participants, other than performance on the Loss Aversion Task, have been published in other reports (Dean et al, 2011(Dean et al, , 2015(Dean et al, , 2018(Dean et al, , 2020Ghahremani et al, 2011Ghahremani et al, , 2012Morales et al, 2012Morales et al, , 2015aPayer et al, 2012;Zorick et al, 2012;Kohno et al, 2014;Ballard et al, 2015a,b;Jones et al, 2016;Okita et al, 2016aOkita et al, ,b,c, 2018Moeller et al, 2018;London et al, 2020). Recruitment utilized online and print advertisements.…”