The illicit use of prescription and over-the-counter drugs to achieve intoxication, commonly referred to as "pharmaceutical highs," has emerged as a significant public health concern in recent years. The article begins by examining the reasons behind the illicit use of prescription and over-the-counter drugs, including the desire for euphoria, relaxation, enhanced cognitive performance, and self-medication for various psychological and physical conditions. It highlights the accessibility and perceived safety of these substances, as well as the influence of social and peer factors, as contributing factors to their misuse. To provide a comprehensive understanding, the review covers a wide range of prescription medicines such as quetiapine, gabapentinoids, Z-drugs, bupropion, venlafaxine, and over-the-counter medicines such as loperamide, dextromethorphan, benzydamine, promethazine, chlorphenamine, diphenhydramine and hyoscine butylbromide,codeine that have emerged as misused and diverted, or already described through the literature, as well as recorded by drug users through online websites reporting new trends and experimentations of drug abuse. It explores the pharmacological effects of these substances and their potential for abuse, dependence, and overdose. Additionally, it discusses the dangers of polydrug use, as individuals often combine multiple substances to potentiate their desired effects. Overall, Healthcare professionals should be aware of potential prescription drugs diversion, recognize misuse cases, consider the possibility of polydrug misuse, and prevent it where possible. Pharmacists can play a key role in preventing and reducing drug abuse and should be involved in evidence-based actions to detect, understand and prevent drug diversion activities and the adverse effects of drug-misuse.