Please use this link to access this publication. Abstract Momentum towards legalization of medical and recreational cannabis drives a convergence between natural cannabinoids and their synthetic counterparts, creating new clinical challenges in a second wave of exposures. This review critically examines the emerging challenges posed by synthetic cannabinoid receptor agonists (SCRAs) and semi-synthetic cannabinoids, emphasizing their clinical implications. SCRAs are potent full agonist activity that have been identified as adulterants in several recreational substances, including cannabis and opioids. Adulteration often leads to unpredictable clinical outcomes and exacerbates the potential for drug interactions. Drawing parallels with other drug epidemics, this paper highlights the urgent need for clinical preparedness to address the nuanced...