Objective:To investigate the effect of Cannabis sativa resin and/or tramadol,two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents.Methods:rats were treated with cannabis resin(5,10 or 20 mg/kg)(equivalent to the active constituent A’-tetrahydrocannabinol),tramadol(5,10 and 20 mg/kg) or tramadol(10 mg/kg)combined with cannabis resin(5,10 and 20 mg/kg) subcutaneously daily for 6 weeks.Acetylcholinesterase(AChE) and butyrylcholinesterase(BChE) activities were measured in brain and serum.We also measured the activity of paraoxonase-1(PONl) in serum of rats treated with these agents.Results:(i) AChE activity in brain increased after 10-20 mg/kg cannabis resin(by 16.3%-36.5%).AChE activity in brain did not change after treatment with 5-20 mg/kg tramadol.The administration of both cannabis resin(5,10 or 20 mg/kg) and tramadol(10 mg/kg) resulted in decreased brain AChE activity by 14.1%,12.9%and 13.6%,respectively;(ii) BChE activity in serum was markedly and dose-dependenlly inhibited by cannabis resin(by 60.9%-76.9%).BChE activity also decreased by 17.6%-36.5%by 10-20mg/kg tramadol and by 57.2%-63.9%by the cannabis resin/tramadol combined treatment;(iii)Cannabis resin at dose of 20 mg/kg increased serum PONl activity by 25.7%.In contrast,tramadol given at 5,10 and 20 mg/kg resulted in a dose-dependent decrease in serum PON1 activity by 19%,36.7%,and 46.1%,respectively.Meanwhile,treatment with cannabis resin plus tramadol resulted in 40.2%,35.8%,30.7%inhibition of PONl activity compared to the saline group.Conclusions:these data suggest that cannabis resin exerts different effects on AChE and BChE activities which could contribute to the memory problems and the decline in cognitive function in chronic users. Objective: To investigate the effect of Cannabis sativa resin and / or tramadol, two commonly drugs of abuse on acetylcholinesterase and butyrylcholinesterase activities as a possible cholinergic biomarkers of neurotoxicity induced by these agents. Methods: rats were treated with cannabis resin (5,10 or (5, 10 and 20 mg / kg) or tramadol (10 mg / kg) combined with cannabis resin (5, 10 and 20 mg / kg) subcutaneously daily for 6 weeks. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in brain and serum. We also measured the activity of paraoxonase- 1 (PONl) in serum of rats treated with these agents. Results: (i) AChE activity in brain increased after 10-20 mg / kg cannabis resin (by 16.3% -36.5%). AChE activity in brain did not change after treatment with 5-20 mg / kg tramadol.The administration of both cannabis resin or 20 mg / kg) and tramadol (10 mg / kg) resulted in decreased brain AChE activity by BChE activity in serum was markedly and dose-dependently inhibited by cannabis resin (by 60.9% -76.9%). BChE activity also decreased by 17.6% -36.5% by 10- 20 mg / kg tramadol and by 57.2% -63.9% by cannabis resin / tramadol combined treatment; (iii) Cannabis resin at dose of 20 mg / kg increased serum PONl activity by 25.7%. In contrast, tramadol given at 5,10 and 20 mg / kg resulted in a dose-dependent decrease in serum PON1 activity by 19%, 36.7%, and 46.1%, respectively. Meanwhile, treatment with cannabis resin plus tramadol resulted in 40.2%, 35.8%, 30.7% inhibition of PONl activity compared to the saline group. Confc: these data suggest that cannabis resin exerts different effects on AChE and BChE activities which could contribute to the memory problems and the decline in cognitive function in chronic users.