Cannabidiol—A friend or a foe?

Cannabidiol (CBD), one of the main actives from Cannabis sativa has been perpetually explored lately for its therapeutic effects. Its main attributes, such as anti-inflammatory and antioxidant effects, snowball into pain management, epilepsy and seizure alleviation, anxiety relief, as well as numerous other implications through the entire metabolism. However, conventional administration routes challenge its therapeutic potential, with reported poor water solubility, hepatic degradation, gastric instability and erratic bioavailability observed in oral administration. As a result, the transdermal delivery systems have emerged as a promising alternative to oral or inhaled routes, offering improved bioavailability and targeted effects. The medical use of CBD throughout Europe, UK, USA or Australia is extensive and usually represented by pharmaceutical preparations recommended after conventional treatment routs fail. The non-medical use is limited by each country's own legislation, a wider range of products being available, but the irregular regulatory landscape coupled with the growing market of cannabinoid-infused products, emphasizes the need for standardized formulations and further clinical research. The present work critically examines the transdermal administration of cannabidiol, explores the skin's potential as a route and the strategies involved in using it for systemic targeting. We highlighted key challenges and provided insights into CBD`s variable bioavailability based on different administration routes and methods, thus compiling a literature-based absorption, distribution, metabolism, and excretion (ADME) study. We also explore the role of the endocannabinoid system, its function in various medical conditions, and the therapeutic effects associated with CBD, particularly in light of the varying legislation across countries. While the breadth of potential benefits is compelling, it is essential to emphasize the ongoing nature of CBD research as individual responses to it can vary significantly.