Comparative Efficacy and Tolerability of Herbal Versus Pharmaceutical Antidepressants in Adults with Depression: A Scoping Review

Background: Depression is a major cause of disability worldwide. Pharmaceutical antidepressants are standard treatments for moderate to severe depression; however, adverse effects, tolerability concerns, and incomplete treatment responses have increased interest in herbal alternatives. Evidence directly comparing herbal and pharmaceutical antidepressants remains inconsistent. Objective: To examine and synthesise evidence on the comparative efficacy, safety, and tolerability of herbal versus pharmaceutical antidepressants in adults with depression. Methods: A scoping review was conducted using MEDLINE, EMBASE, PsycINFO, AMED, CENTRAL, and grey literature sources. Eligible studies were primary comparative clinical studies involving adults aged 18 years and older with depressive disorders or clinically significant depressive symptoms. Data were synthesised according to Joanna Briggs Institute methodology and PRISMA-ScR guidelines. Results: Twenty-one comparative studies met the inclusion criteria. Hypericum perforatum (St John’s wort) was the most frequently investigated herbal intervention, while selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and tricyclic antidepressants were the main pharmaceutical comparators. Standardised Hypericum perforatum preparations demonstrated efficacy comparable to selective serotonin reuptake inhibitors in mild to moderate depression. Pharmaceutical antidepressants, however, showed more consistent benefits in moderate to severe depression. Herbal interventions were generally associated with fewer adverse effects and lower treatment discontinuation rates. Conclusion: Herbal antidepressants, particularly standardised Hypericum perforatum preparations, may offer an effective and better-tolerated treatment option for some adults with mild to moderate depression. However, variations in study design, intervention standardisation, and reporting limit definitive conclusions. Further high-quality comparative research is required to strengthen the evidence base and guide clinical decision-making and support evidence-based treatment recommendations. What this study adds: This review highlights the severity-dependent efficacy and tolerability of pharmaceutical and natural antidepressants. Standardized Hypericum perforatum is identified as a potentially useful and better-tolerated treatment for mild-to-moderate depression, but it also highlights safety issues, especially herb–drug interactions, and important data gaps that need to be studied.