Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study

The use of psychoactive substances, including methamphetamine (MA) may cause changes in DNA methylation. The aim of this study was to examine the effects of MA use on long interspersed element-1 (LINE-1) methylation patterns in association with MA-induced paranoia. This study recruited 123 normal controls and 974 MA users, 302 with and 672 without MA-induced paranoia. The Semi-Structured Assessment for Drug Dependence and Alcoholism was used to assess demographic and substance use variables. Patterns of LINE-1 methylation were assessed in peripheral blood mononuclear cells and a combined bisulfite restriction analysis (COBRA) was used to estimate overall LINE-1 methylation (mC) while COBRA classified LINE-alleles into four patterns based on the methylation status of two CpG dinucleotides on each strand from 5' to 3', namely two methylated (mCmC) and two unmethylated (uCuC) CpGs and two types of partially methylated loci (mCuC that is 5'm with 3'u and uCmC that is 5'u with 3'm CpGs). MA users showed higher % mCuC and % mCuC + uCmC levels than controls. Use of solvents and opioids, but not cannabis and alcohol dependence, significantly lowered % uCmC levels, while current smoking significantly increased % uCuC levels. MA-induced paranoia was strongly associated with changes in LINE-1 partial methylation patterns (lowered % uCmC), heavy MA use, lower age at onset of MA use, and alcohol dependence. Women who took contraceptives showed significantly lower LINE-1 % mC and % mCmC and higher % uCuC levels than women without contraceptive use and men. The results show that MA-induced changes in LINE-1 partial methylation patterns are associated with MA-induced paranoia and could explain in part the pathophysiology of this type of psychosis. It is argued that MA-induced neuro-oxidative pathways may have altered LINE-1 partial methylation patterns, which in turn may regulate neuro-oxidative and immune pathways, which may increase risk to develop MA-induced paranoia.