The occurrence, distribution, and ecological risks of psychoactive substances (PSs) in Qinghai-Tibet Plateau (QTP) was investigated in this study. The surface water samples were collected in July in 2020 from five major water bodies, and 9 PSs were determined by liquid chromatography-mass spectrometry. The mean concentrations of the total PSs were 2.19–96.86 ng/L in lakes and 4.56–34.47 ng/L in rivers. Amphetamine (AMP) was the predominant contaminant both in lakes and rivers with a mean concentration of 12.21 ± 22.76 ng/L and 9.83 ± 6.14 ng/L, respectively. The compositions of PSs in lakes and rivers were significantly different. AMP, methadone (MTD), 3,4-methylenedioxyamphetamine (MDA), and ketamine (KET) were the most detected contaminants in lakes, while in rivers AMP, MDA, heroin (HER), and methamphetamine (METH) were the most detected ones. Concentrations of AMP and MTD, the two predominant drugs, varied spatially, with the decreasing concentration of AMP in the order of Huangshui River > Yamzhog Yumco Lake > Qinghai Lake > Lhasa River > Namco Lake, and of MTD in the order of Qinghai Lake > Namco Lake > Huangshui River > Yamzhog Yumco Lake. The risk quotients (RQs) of PSs ranged from 4.44 × 10−6 to 4.32 × 10−2, indicating a low risk of PSs in the aquatic ecosystem in QTP. Compared with other research in the world, the contamination of psychoactive substances in the Qinghai-Tibet Plateau was at relatively low levels with low ecological risks.
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