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The Qinghai-Tibet Plateau is the third pole of the world, and information on the consumption of psychoactive substances (PSs) in this area is scarce. In this study, we selected Qinghai Province as the research area, and the per capita consumption and prevalence of PSs were investigated using wastewater-based epidemiology. Samples from 17 wastewater treatment plants (WWTPs) in 5 major cities in Qinghai Province were monitored, and 11 PSs were detected by ultra-high performance liquid chromatography-tandem mass spectrometry. Results showed that the target compounds were detected in all samples, with relatively high concentrations of ephedrine (2.1-4825.3 ng/L) and methamphetamine (1.5-295.7 ng/L). The consumption of methamphetamine in Xining City, Haidong City, and Haixi City was up to 78.4, 16.8, and 21.2 mg/1000 inh/d (the PS consumption per 1000 inhabitants in 1 day), respectively, higher than that in the other two cities, which was the result of the different consumption patterns and its relationship with the economic levels of each city. High consumption of methadone (47.9 mg/1000 inh/day) was found in Xining City, which might be related to the methadone maintenance therapy sites in the city. Methamphetamine was the most prevalent drug, with the prevalence ranging from 0.003 (Guoluo) to 0.197% (Xining), and the prevalence of other PSs was low. The ecological risk assessment of PSs in the effluent of WWTPs showed that methadone exerted a low risk to aquatic organisms in three sites, while other substances posed potential risk or no risk. However, the long-term effect of PSs cannot be ignored., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)