Poly-drug use refers to the use of two or more substances at the one time or repeatedly. It is common among both recreational and regular drug users across the world. Poly-drug use is a great contributor to the global number of deaths related to drug overdose. In this case, the likelihood of drug overdose and its pertaining complications in an individual is higher especially when benzodiazepines or alcohol is consumed along with other drugs. According to the recent WHO report, there are 3 patterns of poly-drug use: (1) different substances are taken together to have a cumulative or complementary effect, which is commonly seen among (a) cannabis or cocaine users (the drug may be used in combination with alcohol), (b) heroin users (the drug might be used in combination with benzodiazepines, alcohol or other opioids), (c) cocaine users (the drug might be used in combination with other stimulants); (2) the use of a drug to mitigate the adverse effects of another drug (e.g., use of cocaine and heroin or other opioids); (3) a drug is gradually replacing by another drug due to changes in price or availability (e.g., ecstasy is substituted by mephedrone or other psychoactive substances). Opioids, alcohol, cannabis and cocaine are the most common substances implicated in poly-drug use in different parts of the world. The paradoxical or sometimes amplifying effects of drugs used concurrently make the treatment of the poly-drug use patients extremely challenging. It has been considered important to understand the patterns of poly-drug in different regions to prevent and modify the risk factors and to provide useful guidelines for physicians.