Drugs once classified as ‘substances of abuse’ are now drawing attention in the field of psychiatry as ‘new antidepressants’ for the management of treatment-resistant depression (TRD). Intranasal esketamine was approved by the Food and Drug Administration (FDA) for TRD and stimulants are being used as adjuvant therapy. Clinical studies on the use of cannabinoids, opiates, and psilocybin for depression are currently being conducted. However, even as they are being evaluated for their effectiveness, concern for their abuse potential is growing. In this article, the characteristics of ‘drugs of abuse’ that are approved or being developed as ‘new antidepressants’ are reviewed. Their historical background as mood-enhancers, pharmacological mechanisms, antidepressant effects, and risk of abuse are also discussed.