Psychoactive drugs are classified as contaminants of emerging concern but there is limited information on their fate in surface waters. Here, we studied the fate of three drugs (sertraline, clozapine and citalopram) upon irradiation in the presence of the Pamvotis lake organic matter (WEOM) extracted from sediment under mild conditions. WEOM was characterized by spectral techniques. It showed a percentage of aromaticity of 10.2% and an average molecular weight of 1.7 kDa and had optical characteristics confirming its humic nature. WEOM (5 mgC.L-1) enhanced the drugs phototransformation under simulated solar light by a factor of 2, 4.2 and 16 for sertraline, clozapine and citalopram, respectively. The drastic inhibiting effect of 2-propanol (300.5 mg/L) demonstrated that hydroxyl radical was the key intermediate in these reactions. The photoproduct analysis by UHPLC-HRMS revealed common reactions for the three drugs: oxidation of the N-containing aliphatic ring with or without O atom inclusion and of the aromatic ring with phenols formation, N elimination, and substitution of the halogen by OH. Sertraline and citalopram also underwent elimination of the halogenated ring while for clozapine opening of the N-containing aliphatic ring was observed.