A comprehensive study aimed at monitoring of temporal variability of illicit drugs (heroin, cocaine, amphetamine, MDMA, methamphetamine and cannabis) and therapeutic opiate methadone in a large-sized European city using wastewater-based epidemiology (WBE) was conducted in the city of Zagreb, Croatia, during an 8-year period (2009-2016). The study addressed the impact of different sampling schemes on the assessment of temporal drug consumption patterns, in particular multiannual consumption trends and documented the possible errors associated with the one-week sampling scheme. The highest drug consumption prevalence was determined for cannabis (from 59 ± 18 to 156 ± 37 doses/day/1000 inhabitants 15-64 years), followed by heroin (from 11 ± 10 to 71 ± 19 doses/day/1000 inhabitants 15-64 years), cocaine (from 8.3 ± 0.9 to 23 ± 4.0 doses/day/1000 inhabitants 15-64 years) and amphetamine (from 1.3 ± 0.9 to 21 ± 6.1 doses/day/1000 inhabitants 15-64 years) whereas the consumption of MDMA was comparatively lower (from 0.18 ± 0.08 to 2.7 doses ±0.7 doses/day/1000 inhabitants 15-64 years). The drug consumption patterns were characterized by clearly enhanced weekend and Christmas season consumption of stimulating drugs (cocaine, MDMA and amphetamine) and somewhat lower summer consumption of almost all drugs. Pronounced multiannual consumption trends were determined for most of the illicit drugs. The investigated 8-year period was characterized by a marked increase of the consumption of pure cocaine (1.6-fold), THC (2.7-fold), amphetamine (16-fold) and MDMA (15-fold) and a concomitant decrease (2.3-fold) of the consumption of pure heroin. The heroin consumption decrease was associated with an increase of methadone consumption (1.4-fold), which can be linked to its use in the heroin substitution therapy. The estimated number of average methadone doses consumed in the city of Zagreb was in a good agreement with the prescription data on treated opioid addicts in Croatia.