Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2025 May 2:55:e134.
doi: 10.1017/S0033291725000996.

Comparative efficacy and tolerability of nutraceuticals for depressive disorder: A systematic review and network meta-analysis

Ying-Chih Cheng  1   2   3 , Wei-Lieh Huang  4   5   6   7 , Wen-Yin Chen  2   8   9 , Yu-Chen Huang  3   10   11 , Po-Hsiu Kuo  2   5   12   13   14 , Yu-Kang Tu  2   9   15
Affiliations
Comparative Study

Comparative efficacy and tolerability of nutraceuticals for depressive disorder: A systematic review and network meta-analysis

Ying-Chih Cheng et al. Psychol Med. .

Abstract

Background: Nutraceuticals have been taken as an alternative and add-on treatment for depressive disorders. Direct comparisons between different nutraceuticals and between nutraceuticals and placebo or antidepressants are limited. Thus, it is unclear which nutraceuticals are the most efficacious.

Methods: We conducted a network meta-analysis to estimate the comparative efficacy and tolerability of nutraceuticals for the treatment of depressive disorder in adults. The primary outcome was the change in depressive symptoms, as measured by the standard mean difference (SMD). Secondary outcomes included response rate, remission rate, and anxiety. Tolerability was defined as all-cause discontinuation and adverse events. Frequentist random-effect NMA was conducted.

Results: Hundred and ninety-two trials involving 17,437 patients and 44 nutraceuticals were eligible for inclusion. Adjunctive nutraceuticals consistently showed better efficacy than antidepressants (ADT) alone in outcomes including SMD, remission, and response. Notable combinations were Eicosapentaenoic acid + Docosahexaenoic Acid plus ADT (EPA + DHA + ADT) (SMD 1.04, 95% confidence interval 0.64-1.44), S-Adenosyl Methionine (SAMe) + ADT (0.99, 0.31-1.68), curcumin + ADT (1.03, 0.55-1.51), Zinc + ADT (1.59, 0.63-2.55), tryptophan + ADT (1.24, 0.32-2.16), and folate + ADT (0.64, 0.17-1.10). Additionally, four nutraceutical monotherapies demonstrated superior efficacy compared to ADT: EPA + DHA (0.6, 0.32-0.88), SAMe (0.52, 0.18-0.87), curcumin (0.62, -0.17 to 1.40) and saffron (0.69, 0.34-1.04). It is noted that EPA + DHA, SAMe, and curcumin showed strong performance as either monotherapies or adjuncts to ADT. Most nutraceuticals showed comparable tolerability to placebo.

Conclusions: This extensive systematic review and NMA of nutraceuticals for treating depressive disorders indicated a number of nutraceuticals that could offer benefits, either as adjuncts or monotherapies.

Keywords: depression; network meta-analysis; nutraceuticals; randomized controlled trials.

PubMed Disclaimer

Conflict of interest statement

The authors declare none.

Figures

Figure 1.
Figure 1.
Study selection flowchart. a Other sources included references mining of the included studies.
Figure 2.
Figure 2.
Network diagram for change in depressive symptoms. a Lines between nodes represent direct comparisons between trials, and the circle size is proportional to the size of the population that received each treatment. Line thickness is proportional to the number of studies providing data for the comparison. b Abbreviations: ADT: antidepressant; Ca: calcium; CoQ10: co-enzyme Q10; DHA: docosahexaenoic acid; E amoenum: Echium amoenum; EPA: eicosapentaenoic acid; Fe: ferrum; Mg: magnesium; PEA: palmitoylethanolamide; R rosea: Rhodiola rosea; SAMe: S-adenosyl methionin; SJW: St. John’s wort; vitamin B1: thiamine; vitamin B6: pyridoxine; vitamin B7: biotin; vitamin B: vitamin B complex; vitamin B12: cobalamin; vitamin C: Ascorbic acid; vitamin D: cholecalciferol; 5HTP: 5-hydroxytryptophan.
Figure 3.
Figure 3.
Forest plot for change in depressive symptoms. a Denotes significance at p < 0.05. b Abbreviations: ADT: antidepressant; Ca: calcium; CI: confidence interval; CoQ10: co-enzyme Q10; DHA: docosahexaenoic acid; E amoenum: Echium amoenum; EPA: eicosapentaenoic acid; Fe: ferrum; Mg: magnesium; PEA: palmitoylethanolamide; R rosea: Rhodiola rosea; SAMe: S-adenosyl methionine; SMD: standard mean difference; SJW: St. John’s wort; vitamin B1: thiamine; vitamin B6: pyridoxine; vitamin B7: biotin; vitamin B: vitamin B complex; vitamin B12: cobalamin; vitamin C: ascorbic acid; vitamin D: cholecalciferol; 5HTP: 5-hydroxytryptophan.
Figure 4.
Figure 4.
Forest plot for response rate. a Denotes significance at p < 0.05. b Abbreviations: ADT: antidepressant; CI: confidence interval; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; OR: odds ratio; PEA: palmitoylethanolamide; SAMe: S-adenosyl methionine; SJW: St. John’s wort; vitamin B1: thiamine; vitamin B6: pyridoxine; vitamin B12: cobalamin; vitamin C: ascorbic acid; vitamin D: cholecalciferol; 5HTP: 5-hydroxytryptophan.
Figure 5.
Figure 5.
Forest plot for remission rate. a Denotes significance at p < 0.05. b Abbreviations: ADT: antidepressant; CI: confidence interval; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; PEA: palmitoylethanolamide; SAMe: S-adenosyl methionine; SJW: St. John’s wort; vitamin B1: thiamine; vitamin B6: pyridoxine; vitamin B12: cobalamin; vitamin C: ascorbic acid; vitamin D: cholecalciferol; 5HTP: 5-hydroxytryptophan.
See this image and copyright information in PMC

References

    1. Akhondzadeh Basti, A., Moshiri, E., Noorbala, A. A., Jamshidi, A. H., Abbasi, S. H., & Akhondzadeh, S. (2007). Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: A pilot double-blind randomized trial. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 31(2), 439–442. 10.1016/j.pnpbp.2006.11.010. - DOI - PubMed
    1. Apaydin, E. A., Maher, A. R., Shanman, R., Booth, M. S., Miles, J. N., Sorbero, M. E., & Hempel, S. (2016). A systematic review of St. John’s wort for major depressive disorder. Systematic Reviews, 5(1), 148. 10.1186/s13643-016-0325-2. - DOI - PMC - PubMed
    1. Bauer, M., Pfennig, A., Severus, E., Whybrow, P. C., Angst, J., Moller, H. J., & World Federation of Societies of Biological Psychiatry. Task Force on Unipolar Depressive Disorders. (2013). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders. The World Journal of Biological Psychiatry, 14(5), 334–385. 10.3109/15622975.2013.804195. - DOI - PubMed
    1. Bull, S. A., Hunkeler, E. M., Lee, J. Y., Rowland, C. R., Williamson, T. E., Schwab, J. R., & Hurt, S. W. (2002). Discontinuing or switching selective serotonin-reuptake inhibitors. Annals of Pharmacotherapy, 36(4), 578–584. 10.1345/aph.1A254. - DOI - PubMed
    1. Cenit, M. C., Nuevo, I. C., Codoñer-Franch, P., Dinan, T. G., & Sanz, Y. (2017). Gut microbiota and attention deficit hyperactivity disorder: New perspectives for a challenging condition. European Child & Adolescent Psychiatry, 26(9), 1081–1092. 10.1007/s00787-017-0969-z. - DOI - PubMed

MeSH terms

Substances