Background: Methamphetamine use disorders (MAUD) can substantially jeopardize public security due to their high-risk social psychology and behavior. Given that the dopamine reward system is intimately associated with MAUD, we investigated the association of single nucleotide polymorphisms (SNPs), as well as methylation status of DRD4, COMT genes and paranoid, motor impulsive symptoms in MAUD patients. Methods: A total of 189 MAUD patients participated in our study. Samples of peripheral blood were used to detecte for 3 SNPs and levels of 35 CpG units of methylation in the DRD4 gene’s promoter region, 5 SNPs and 39 CpG units in the COMT gene. Results: MAUD patients with rs1800955 C allele have a lower percentage of paranoid symptom than those with rs1800955 TT. Individuals with paranoid symptom exhibited reduced methylation degree at particular DRD4 CpG2.3 unit. The interaction of the DRD4 rs1800955 C allele and the reduced DRD4 CpG2.3 methylation degree resulted in the lower occurrence of the paranoid symptom. Meanwhile, those with COMT rs4818 CC allele have lower motor impulsivity scores in MAUD patients, but greater COMT methylation levels in the promotor region and methylation degree at COMT CpG 51.52 unit. Therefore, based only on COMT rs4818 CC polymorphism, there was a negative correlation between COMT methylation and motor impulsivity scores in the MAUD patients. Conclusions: Our results found that the combination of SNP genotyping and methylation status of the DRD4 and COMT genes may serve as biological indicators to evaluate the prevalence of relatively high-risk psychotic symptoms in MAUD patients.