Background: Methamphetamine (METH) dependence becomes the major public health concern for many countries. METH is an abusive stimulant with various psychophysiological effects to its abusers. METH activates the human&#39;s brain reward circuitry and addiction, by increasing dopamine (DA) and serotonin (5-HT) levels in the synaptic cleft. </P><P> Objective: We investigated allelic variants of 5-HTTLPR, 5-HT1A C(-1019)G, 5-HT2A (102 T/C), and DRD2 Taq IA gene polymorphisms. </P><P> Methods: Subjects were recruited and met the DSM-IV criteria of METH dependence. They were screened with Diagnostic Interview for Genetic Study (DIGS), Family Interview for Genetic Study (FIGS), and a short research questionnaire. Blood samples were collected, and DNA was extracted from leukocytes and PCR-amplified. The PCR products were then digested with enzymes: Hpy CH4IV, MspI, and Taq I restriction enzyme, respectively for 5-HT1A C(-1019)G, 5-HT2A (102 T/C), and DRD2 Taq IA. The genotypes were assigned on agarose gel size fractionation and allele identification. </P><P> Results: The results indicated that METH-dependent patients were likely to be poly-substance abusers. Genetic results showed that there were no differences between genetic variation of 5-HTTLPR, 5-HT1A C(-1019)G, and DRD2 Taq IA gene polymorphisms and METH dependence. For 5-HT2A 102T/C, T/C genotype was found to be significantly higher in METHdependent patients compared to healthy controls. Additionally, there was a significant difference for T allele of 5-HT2A 102T/C in METH-dependent patients with comorbidity of three prominent psychotic features: METH-induced psychosis, suicidal behaviors, and depressive symptoms. </P><P> Conclusion: These results suggest that the METH dependence, psychiatric comorbidity, and genetic variation can pose a challenge in the treatment of METH-dependent patients.