Xylazine, an alpha-2-adrenergic agonist, has been increasingly linked to substance use and overdose crises, yet there is a significant lack of understanding about its effects on humans. As a result, it is crucial to recognize and manage symptoms of xylazine toxicity, withdrawal, and overdose effectively. To address this knowledge gap, a systematic review was conducted to consolidate existing literature on the management of xylazine intoxication, withdrawal, overdose, and dependence in humans. The review aimed to identify gaps in current knowledge and propose evidence-based actions for managing patients affected by xylazine. By examining published literature from 1957 to 2024, the review sought to provide a comprehensive understanding of xylazine's effects and potential treatment options. The systematic review included 34 studies, which revealed that xylazine misuse is commonly seen among men aged 19-45 years, often in combination with other substances. The doses of xylazine ranged from 40 to 4300 mg, with no established toxic dosing threshold. The review found that supportive care for xylazine toxicity, withdrawal, and overdose typically involves treatment with medications such as naloxone, alpha-2 agonists, and GABAergic medications. However, it is significant to note that there is currently no antidote or evidence-based treatment recommendations for xylazine overdose. The review highlights the need for further research to address the gaps in xylazine management, including the development of standardized treatment protocols and antidotes. By consolidating existing knowledge and proposing guidelines for xylazine management, this review aims to serve as a reference for healthcare providers to improve patient outcomes and inform ongoing research efforts. Ultimately, the review's findings will contribute to a better understanding of xylazine's effects and the development of effective treatment strategies to address the growing public health crisis surrounding xylazine. Link: https://pubmed.ncbi.nlm.nih.gov/40476542/