Systematic analysis of the pharmacology of saffron extracts in the context of complex pharmacotherapy for depression

Pharmacotherapy for depression is in urgent need of effective and safer drugs. A promising area of research in this field is the use of pharmaceutically standardized saffron extracts containing bioactive substances such as safranal, crocin, bioflavonoids and their derivatives. This paper presents the results of a systematic computer analysis of 3,157 publications on the pharmacology of saffron extracts, with an emphasis on the results of studies of the antidepressant properties of the extracts. Unlike most synthetic antidepressants, which narrowly target a particular neurotransmission system, the molecular components of saffron extracts have a much more complex modulating effect on neurotransmission. In addition, standardised saffron extracts exhibit pronounced antioxidant, anti-inflammatory (NF- κB inhibition) and neurotrophic effects (primarily through increased levels of the brain-derived neurotrophic factor – BDNF), which is also important for the pathogenetic treatment of depressive states. Randomised clinical trials and their meta-analyses show that preparations based on standardised saffron extracts, both as part of complex therapy and as monotherapy, have therapeutic effects comparable to those of known antidepressants (imipramine, fluoxetine, etc.). The available data from fundamental and evidence-based studies suggest that saffron extracts can be used by patients taking various classes of antidepressants without adverse effects. Moreover, the use of saffron extracts may increase the safety of antidepressant therapy. Further research into the combination of saffron extract standardised for safranal with the 'psychobiotic' bifidobacterial strain Bifidobacterium longum 1714 and vitamin B₆ is promising.

1. Ahmad S, Azhar A, Tikmani P, et al. A randomized clinical trial to test efficacy of chamomile and saffron for neuroprotective and anti-inflammatory responses in depressive patients. Heliyon. 2022 Sep 30;8(10):e10774. doi: 10.1016/j.heliyon.2022.e10774

2. Nurzynska-Wierdak R. Plants with Potential Importance in Supporting the Treatment of Depression: Current Trends, and Research. Pharmaceuticals (Basel). 2024 Nov 6;17(11):1489. doi: 10.3390/ph17111489

3. Cheng YC, Huang WL, Chen WY, et al. Comparative efficacy and tolerability of nutraceuticals for depressive disorder: A systematic review and network meta-analysis. Psychol Med. 2025 May 2;55:e134. doi: 10.1017/S0033291725000996

4. Yan JH, Tang KW, Zhong M, Deng NH. Determination of chemical components of volatile oil from Cuminum cyminum L. by gas chromatography-mass spectrometry. Se Pu. 2002 Nov;20(6):569-72.

5. Negbi M. Saffron: Crocus sativus L. CRC Press; 1999. ISBN 978-90-5702-394-1

6. Hosseinzadeh H, Nassiri-Asl M. Avicenna's (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): a review. Phytother Res. 2013 Apr;27(4):475-83. doi: 10.1002/ptr.4784

7. Shen CL, Hassan T, Presto P, et al. Novel Insights into Dietary Bioactive Compounds and Major Depressive Disorders: Evidence from Animal Studies and Future Perspectives. J Nutr. 2025 Apr 22:S0022-3166(25)00190-7. doi: 10.1016/j.tjnut.2025.04.006

8. Fazilat S, Tahmasbi F, Mirzaei MR, et al. A systematic review on the use of phytotherapy in managing clinical depression. Bioimpacts. 2024 Aug 11;15:30532. doi: 10.34172/bi.30532

9. Siddiqui MJ, Saleh MSM, Basharuddin SNBB, et al. Saffron (Crocus sativus L.): As an Antidepressant. J Pharm Bioallied Sci. 2018 Oct-Dec;10(4):173-80. doi: 10.4103/JPBS.JPBS_83_18

10. Hosseinzadeh H, Talebzadeh F. Anticonvulsant evaluation of safranal and crocin from Crocus sativus in mice. Fitoterapia. 2005 Dec;76(7-8):722-4. doi: 10.1016/j.fitote.2005.07.008

11. Hosseinzadeh H, Sadeghnia HR. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci. 2005 Aug 22;8(3):394-9.

12. Escribano J, Alonso GL, Coca-Prados M, Fernandez JA. Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer Lett. 1996 Feb 27;100(1-2):23-30. doi: 10.1016/0304-3835(95)04067-6

13. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med. 2004 Sep 2;4:12. doi: 10.1186/1472-6882-4-12

14. Nanda S, Madan K. The role of Safranal and saffron stigma extracts in oxidative stress, diseases and photoaging: A systematic review. Heliyon. 2021 Feb 10;7(2):e06117. doi: 10.1016/j.heliyon.2021.e06117

15. Torshin IY. On solvability, regularity, and locality of the problem of genome annotation. Pattern Recognit Image Anal. 2010;20:386-95. doi: 10.1134/S1054661810030156

16. Gromova OA, Torshin IYu, Kobalava ZhD, et al. Deficit of Magnesium and States of Hypercoagulation: Intellectual Analysis of Data Obtained From a Sample of Patients Aged 18-50 years From Medical and Preventive Facilities in Russia. Kardiologiia. 2018;58(4):22-35. doi: 10.18087/cardio.2018.4.1010 (In Russ.).

17. Torshin IYu, Gromova OA, Stakhovskaya LV, et al. Analysis of 19.9 million publications from the PubMed/MEDLINE database using artificial intelligence methods: approaches to the generalizations of accumulated data and the phenomenon of “fake news”. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2020;13(2):146-63. doi: 10.17749/2070-4909/farmakoekonomika.2020.021 (In Russ.).

18. Sen D, Rathee S, Pandey V, Jain SK. Exploring Saffron's Therapeutic Potential: Insights on Phytochemistry, Bioactivity, and Clinical Implications. Curr Pharm Des. 2024 Oct 16. doi: 10.2174/0113816128337941240928181943

19. Dobrek L, Glowacka K. Depression and Its Phytopharmacotherapy – A Narrative Review. Int J Mol Sci. 2023 Mar 1;24(5):4772. doi: 10.3390/ijms24054772

20. Matraszek-Gawron R, Chwil M, Terlecki K, Skoczylas MM. Current Knowledge of the Antidepressant Activity of Chemical Compounds from Crocus sativus L. Pharmaceuticals (Basel). 2022 Dec 30;16(1):58. doi: 10.3390/ph16010058

21. Siddiqui SA, Ali Redha A, Snoeck ER, et al. Anti-Depressant Properties of Crocin Molecules in Saffron. Molecules. 2022 Mar 23;27(7):2076. doi: 10.3390/molecules27072076

22. Yang W, Qiu X, Wu Q, et al. Active constituents of saffron (Crocus sativus L.) and their prospects in treating neurodegenerative diseases (Review). Exp Ther Med. 2023 Apr 3;25(5):235. doi: 10.3892/etm.2023.11934

23. Patel KS, Dharamsi A, Priya M, et al. Saffron (Crocus sativus L.) extract attenuates chronic scopolamine-induced cognitive impairment, amyloid beta, and neurofibrillary tangles accumulation in rats. J Ethnopharmacol. 2024 May 23;326:117898. doi: 10.1016/j.jep.2024.117898

24. Amin F, Ahmad S, Wasim M, et al. Antidepressive and anxiolytic effects of a combination of Saffron and Chamomile in rats and their relationship with serotonin using methods. J Tradit Chin Med. 2025 Feb;45(1):49-56. doi: 10.19852/j.cnki.jtcm.2025.01.005

25. Corridori E, Salviati S, Demontis MG, et al. Therapeutic Potential of Saffron Extract in Mild Depression: A Study of Its Role on Anhedonia in Rats and Humans. Phytother Res. 2025 Mar;39(3):1277-91. doi: 10.1002/ptr.8424

26. Tashakori A, Hassanpour S, Vazir B. Protective effect of crocin on cuprizoneinduced model of multiple sclerosis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug;396(8):1713-25. doi: 10.1007/s00210-02302424-6

27. Ghasemzadeh Rahbardar M, Hosseinzadeh H. A review of how the saffron (Crocus sativus) petal and its main constituents interact with the Nrf2 and NF- κB signaling pathways. Naunyn Schmiedebergs Arch Pharmacol. 2023 Sep;396(9):1879-909. doi: 10.1007/s00210-023-02487-5

28. Zhou Y, Chen Z, Su F, et al. NMR-based metabolomics approach to study the effect and related molecular mechanisms of Saffron essential oil against depression. J Pharm Biomed Anal. 2024 Sep 1;247:116244. doi: 10.1016/j.jpba.2024.116244

29. Lin S, Chen Z, Wu Z, et al. Involvement of PI3K/AKT Pathway in the Rapid Antidepressant Effects of Crocetin in Mice with Depression-Like Phenotypes. Neurochem Res. 2024 Feb;49(2):477-91. doi: 10.1007/s11064-023-04051-2

30. Madan K, Nanda S. In-vitro evaluation of antioxidant, anti-elastase, anti-collagenase, anti-hyaluronidase activities of safranal and determination of its sun protection factor in skin photoaging. Bioorg Chem. 2018 Apr;77:159-67. doi: 10.1016/j.bioorg.2017.12.030

31. Shafiee M, Arekhi S, Omranzadeh A, Sahebkar A. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord. 2018 Feb;227:330-7. doi: 10.1016/j.jad.2017.11.020

32. Lopresti AL, Smith SJ, Marx W, et al. An examination into the effects of a saffron extract (Affron) on mood and general wellbeing in adults experiencing low mood: a randomised, double-blind, placebo-controlled trial. J Nutr. 2025 May 23:S0022-3166(25)00306-2. doi: 10.1016/j.tjnut.2025.05.024

33. Lopresti AL, Smith SJ, Hood SD, Drummond PD. Efficacy of a standardised saffron extract (Affron®) as an add-on to antidepressant medication for the treatment of persistent depressive symptoms in adults: A randomised, double-blind, placebo-controlled study. J Psychopharmacol. 2019 Nov;33(11):1415-27. doi: 10.1177/0269881119867703

34. Ghajar A, Neishabouri SM, Velayati N, et al. Crocus sativus L. versus Citalopram in the Treatment of Major Depressive Disorder with Anxious Distress: A Double-Blind, Controlled Clinical Trial. Pharmacopsychiatry. 2017 Jul;50(4):152-60. doi: 10.1055/s-0042-116159

35. Musazadeh V, Zarezadeh M, Faghfouri AH, et al. Saffron, as an adjunct therapy, contributes to relieve depression symptoms: An umbrella meta-analysis. Pharmacol Res. 2022 Jan;175:105963. doi: 10.1016/j.phrs.2021.105963

36. Joodaki M, Radahmadi M, Alaei H. Comparative Evaluation of Antidepressant and Anxiolytic Effects of Escitalopram, Crocin, and their Combination in Rats. Adv Biomed Res. 2024 Oct 28;13:99. doi: 10.4103/abr.abr_259_23

37. Nasseri S, Hajrasouliha S, Vaseghi S, Ghorbani Yekta B. Interaction effect of crocin and citalopram on memory and locomotor activity in rats: an insight into BDNF and synaptophysin levels in the hippocampus. Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep;397(9):6879-88. doi: 10.1007/s00210-02403069-9

38. Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. J Integr Med. 2013 Nov;11(6):377-83. doi: 10.3736/jintegrmed2013056

39. Pages-Garcia C, De Almagro MC, Ruiz-Moreno J, De Castellar R. Effectiveness of a Saffron and Withania Supplement on Mood in Women With Mild-to-Moderate Anxiety During the COVID-19 Lockdown. Depress Anxiety. 2024 Nov 11;2024:3661412. doi: 10.1155/2024/3661412

40. Torshin IYu, Gromova OA, Vanchakova NP, Semyonov VA. Comparative analysis of microbiome indicators in patients with mental disorders and in healthy volunteers. Eksperimental'naya i klinicheskaya gastroenterologiya = Experimental and Clinical Gastroenterology. 2022;204(8):92-105 (In Russ.).

41. Jacobs JP, Mayer EA. Psychobiotics: Shaping the Mind With Gut Bacteria. Am J Gastroenterol. 2019 Jul;114(7):1034-5. doi: 10.14309/ajg.0000000000000281

42. Moloney GM, Long-Smith CM, Murphy A, et al. Improvements in sleep indices during exam stress due to consumption of a Bifidobacterium longum. Brain Behav Immun Health. 2020 Nov 13;10:100174. doi: 10.1016/j.bbih.2020.100174

43. Patterson E, Tan HTT, Groeger D, et al. Bifidobacterium longum 1714 improves sleep quality and aspects of well-being in healthy adults: a randomized, double-blind, placebo-controlled clinical trial. Sci Rep. 2024 Feb 14;14(1):3725. doi: 10.1038/s41598-02453810-w

44. Torshin IIu, Gromova OA, Gusev EI. Mechanisms of antistress and antidepressive effects of magnesium and pyridoxine. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2009;109(11):107-11 (In Russ.).

45. Amara RO, Aburawi SM. Pyridoxine effect on the antidepressant action of imipramine in albino mice. Saudi Med J. 2008 Nov;29(11):1554-7.

46. Calderon-Guzman D, Hernandez-Islas JL, Espitia-Vazquez I, et al. Pyridoxine, regardless of serotonin levels, increases production of 5hydroxytryptophan in rat brain. Arch Med Res. 2004 Jul-Aug;35(4):271-4. doi: 10.1016/j.arcmed.2004.03.003

47. Maratha S, Sharma V, Walia V. Possible involvement of NO-sGC-cGMP signaling in the antidepressant like effect of pyridoxine in mice. Metab Brain Dis. 2022 Jan;37(1):173-83. doi: 10.1007/s11011-02100858-6