St. John's Wort (Hypericum perforatum/ Cantarion) has been well-studied which has been showed to have antidepressant, antiviral, and antibacterial effects. St John's Wort gained popularity as an alternative treatment for mild to moderate depression. On the other hand, the neuropeptide, orphanin FQ/nociceptin (OFQ/N), is expressed in both neuronal and non-neuronal tissue. In the brain, OFQ/N has been investigated in relation to stress, anxiety, learning and memory, and addiction. The purpose opf this article is to review the current pharmacological, and clinical papers on St. John's wort, to provide information on orphanin FQ/nociceptin and finally to evaluate probable interaction between two.