© 2020 Elsevier LtdWastewater-based drug monitoring is a complementary tool that has been used worldwide in recent years, and many cities have periodically reported monitoring results. However, this study is the first to analyze drugs in wastewater in a single city with a high population during four periods simultaneously from 14 treatment plants. The aim was to estimate the consumption of conventional illicit drugs [amphetamine (AMP), methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), cannabis, cocaine, and heroin], tobacco, and alcohol in 2019 for quarterly periods in Istanbul city, which has a population of almost 20 million, to aid in implementing evidence-based measures. Additionally, the seasonal variations among the 14 wastewater treatment plants and their weekday/weekend comparison of drug use patterns and consumption per substance were examined. Solid phase extraction was followed by liquid chromatography-tandem mass spectrometry and a previously validated method was enhanced by adding new parameters (morphine, cotinine, and ethyl sulfate), and satisfactory results were obtained. In this study, alcohol, nicotine, and cannabis had the highest estimated per capita consumption with mean values of 29655.3 mL/1000 inh/day, 5507.6 mg/1000 inh/day and 3607.0 mg/1000 inh/day, respectively. These results were followed by heroin and cocaine consumption with mean values of 557.0 and 200.9 mg/1000 inh/day, respectively, whereas AMP-type stimulants had the lowest values among the targeted substances. METH and cannabis were also highly consumed drugs when compared with the results of other metropolitan cities, whereas heroin consumption was remarkably high owing to Turkey's location on a possible heroin trafficking route. Because Istanbul is the business center of the country and has the potential to attract tourists in all four seasons, meaningful seasonal consumption differences were not observed for all substances.