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Hypericum perforatum (Hypericaceae), known as Saint John’s wort (SJW), has been used in different systems of traditional medicine such as Chinese traditional medicine, Greek traditional medicine, and Islamic traditional medicine. The plant and its active constituents such as hyperforin and hypericin have a wide range of medicinal uses, particularly as anti-depressant, wound-healing, and antibacterial agents. In recent decades, many clinical trials have been performed to investigate the safety and efficacy of this medicinal plant. However, to the best on our knowledge, there is no comprehensive review article in this regard. In the current study, we aim to have a comprehensive review of the clinical trials of SJW to evaluate its efficacy and safety as well as its application in traditional medicine. Clinical studies investigating the safety, interactions, and efficacy of SJW were identified and summarized, including …