polysubstance use polysubstance use polysubstance use or poly drug use refers to the use of combined psychoactive substances. polysubstance use may be used for entheogenic, recreational, or off-label indications, with both legal and illegal substances. in many cases one drug is used as a base or primary drug, with additional drugs to leaven or compensate for the side effects, or tolerance, of the primary drug and make the experience more enjoyable with drug synergy effects, or to supplement for primary drug when supply is low. polysubstance usecaffeinated alcoholic beverages, such as these caffè corretto cocktails based on espresso and liquor are widespread and legal.specialtypsychiatrycomplicationscombined drug intoxication, drug overdose not to be confused with polysubstance abuse. for combination of pharmaceuticals, see combination drug and polypharmacy. ayahuasca being prepared in the napo region of ecuador a spoonful of promethazine/​codeine cough syrup showing the characteristic purple color that gave rise to the name purple drank. common combinations main article: list of polysubstance combinations the most common psychoactive substances are alcohol, caffeine, cannabis, and nicotine (tobacco, and nicotine replacement therapy). some of the absolutely most common polysubstance combinations are: alcohol combined with cannabis — known as cross-fading and may easily cause spins in people who are drunk and smoke potent cannabis. ayahuasca: dmt combined with maois. caffeinated alcoholic drinks combination drugs