Orexin has been suggested to play a role in regulating the reward circuits and enhancing drug-seeking behaviors; however, its role in methamphetamine (METH) addiction remains unclear. We previously found that blood orexin-A levels are upregulated in individuals with recent METH exposure. Whether the levels would be altered following withdrawal is unknown. In this study, we compared the levels of serum orexin-A in individuals who use METH between the acute withdrawal (AW) phase and the subacute withdrawal (SAW) phase at baseline (T1) and examined the alterations in these levels after 2 weeks of abstinence (T2). In total, 60 participants (51 men and 9 women) were enrolled in the study; 20 participants with METH-positive urine test results were included in the AW group, and 40 participants with METH-negative urine test results who had self-reportedly last taken METH within the preceding 1–2 months were included in the SAW group. Serum orexin-A levels were measured using enzyme-linked immunosorbent assay. No significant differences in orexin-A levels were observed between the AW and SAW groups at baseline (p = .06). After 2 additional weeks of abstinence, the levels decreased significantly in the SAW group (0.58 ± 0.13 ng/mL) but not in the AW group (0.50 ± 0.14 ng/mL, p = .004). Our results demonstrated that orexin-A levels might decrease after a longer period of METH withdrawal, indicating that the orexin system is dysregulated in the addictive process of METH. (PsycInfo Database Record (c) 2021 APA, all rights reserved)