Saffron refers to the stigmas of a flower crocus sativus. 1 lb of saffron costs USD3,000-6,000. It has been used as a coloring agent, flavor enhancer and medicine for more than five thousand years. Recent scientific studies had revealed its biological properties beneficial for health.

1. SPICE AS MEDICINE
SAFFRON
CROCUS SATIVUS
By
Kevin KF Ng, MD., PhD.,
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL., USA
Email: kevinng68@gmail.com
A Slide Presentation for HealthCare Providers Dec 2022

2. Presentation Outline
▪ Poll result on “Why is saffron so costly?”
▪ What is saffron?
▪ High cost of saffron
▪ History
▪ Global production of saffron
▪ Anatomy, nutrient and phytochemical composition
▪ Bioavailability, preclinical and clinical studies
▪ Toxicity
▪ Commercial products
▪ Summary

3. Polling result on “Why is saffron so costly” in LinkedIn from
11/27/2022 to 12/04/2022

4. What is saffron?
▪ Saffron is a feminine name of Arabic origin, meaning “yellow flower.”
▪ Saffron is also known as “spice of happiness” and “red gold”
▪ The word "saffron" is derived from the Latin word safranum via the
12th-century Old French term safran. The French was borrowed from
Arabic ‫ان‬َ‫ر‬َ‫ف‬ْ‫ع‬َ‫ز‬
( za'farān), and ultimately from Persian ‫ران‬َ‫پ‬‫ر‬ َ‫ز‬
( zarparān)
which literally means "golden leaves".

5. Cost of 1 gram of gold vs 1 gram of saffron
1 gram of gold US$60-80.00 1 gram of saffron US$6-30.00
$74.90 $17.82
https://www.amazon.com/s?k=1+gram+ssffon&crid=3PX9HXXRH8JJJ&spr
efix=1+gram+ssffon%2Caps%2C77&ref=nb_sb_noss
https://www.bullionbypost.com/gold-bars/1-
gram-gold-bar/1-gram-gold-bar-best-value/

6. Why is saffron so costly?
▪ Flowers bloom once a year
▪ It requires 370-470 hours to harvest 1 kg of stigmas
from 15,000-16,000 flowers
https://www.theguardian.com/world/gallery/2007/nov/23/iran.india

7. ▪ ORIGIN OF SAFFRON
▪ GLOBAL DISTRIBUTION
▪ SCIENTIFIC CLASSIFICATION
▪ SCIENTIFIC PUBLICATIONS

8. Origin of saffron
▪ Saffron is native to Southwest Asia but was first cultivated in Greece.
▪ Some historians believe that saffron came to China with Mongol invaders from
Persia.
▪ Saffron is mentioned in Ancient Cultures (Akkadian, Mesopotamia, Greece, Rome),
the Old testament and ancient Chinese medical text, Shen Nong Ben Cao Jin, the
Divine Farmer’s Materia Medica around 300–200 BC.

9. World production of Saffron (crocus sativus)
https://commons.wikimedia.org/wiki/File:Saffron_crocus_sativus_modern_world_production.jpg

10. Global Saffron Market (2018)
https://behinexir.com/global-saffron-market/ https://www.sadafpack.com/blog/which-countries-export-saffron/

11. Scientific classification of saffron

12. Number of publication on Saffron and its derivatives in PubMed
up to 2022
Source:PubMed
Total=5,446

13. ▪ ANATOMY OF SAFFRON
▪ NUTRIENTS
▪ BIOACTIVE COMPOUNDS

14. Anatomy of a crocus flower
https://www.laboiteny.com/blogs/single-spices/saffron
Stigma
Stamen

15. Characteristic features of saffron
https://thescentcompany.com/en/saffron/

16. Nutrients and bioactive compounds in saffron

17. Chemical composition of saffron (2010)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249922/

18. Nutrient composition of dried saffron per 1 tbsp (2.1 g)
https://en.wikipedia.org/wiki/Saffron#Western_Europe

19. Proximate analysis of saffron (2010)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249922/

20. ▪ PHYSICOCHEMICAL PROPERTIES
▪ PHARMACOKINETICS

21. Nutrients and bioactive compounds in saffron
Water soluble
Bitter
Volatile

22. Crocin and its derivatives

23. Conversion of crocin to crocetin by intestinal microbiota. (2020)
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692355/

24. Absorption and distribution of crocetin in organs(2020)
Adapted from https://www.frontiersin.org/articles/10.3389/fphar.2021.745683/full#T2
Crocetin

25. Cumulative concentration versus time profiles of crocin (A,C,E) and crocetin (B,D,F) in
plasma (A,B), urine (C,D) and feces (E,F) after single oral administration of rats with
600 mg/kg crocin to control and antibiotic pre-treated rats.
Each value represents the mean ± S.E. of 5 animals. (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692355/
Crocin Crocetin

26. Pharmacokinetic parameters of crocin and crocetin following single
oral administration to control and antibiotic-treated rats (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692355/
Evidence that crocin is metabolized to crocetin in the intestinal tract

27. PRECLINICAL STUDIES

28. Pharmacological properties of saffron and its derivatives in
Preclinical studies

29. The Effect of Chronic Administration of Safranal on
Systolic Blood Pressure in Rats (2015)
Mean systolic blood pressure (MSBP) in response to
various doses of crocin in normotensive and
hypertensive rats at the end of nine weeks. Each
value is the mean ± SEM of six experiments. One-
way ANOVA, Tukey Krumer,**P<0.01 and
***P<0.001vs DOCA plus normal saline treated rats,
##P<0.01 and ###P<0.001 vs DOCA plus
spironolactone
https://www.researchgate.net/publication/275361853_The_Effect_of_Ch
ronic_Administration_of_Safranal_on_Systolic_Blood_Pressure_in_Rats

30. Crocin exhibits an antihypertensive effect in a rat model of
gestational hypertension (2021)
https://www.nature.com/articles/s41440-020-00609-7

31. Effect of crocin on glucose and glycated proteins in
Streptozotocin-induced diabetic rats(2012)
https://www.academia.edu/30094790/Effect_of_Crocin_on_the_Insulin_
Resistance_and_Lipid_Profile_of_Streptozotocin_Induced_Diabetic_Rats
H), control group
(H+C) treated with crocin),
(D) diabetic group and
(D+C50) or (D+C100) diabetic groups treated with crocin, 50mg/kg, or100mg/kg
Glucose AGE (advanced glycation end product) HbA1c

32. Effect of crocin on the insulin resistance of streptozotocin-
induced diabetic rats (2012)
https://www.academia.edu/30094790/Effect_of_Crocin_on_the_Insulin
_Resistance_and_Lipid_Profile_of_Streptozotocin_Induced_Diabetic_Rats
(H), control group
(H+C) treated with crocin),
(D) diabetic group and
(D+C50) or (D+C100) diabetic groups treated with crocin,
50mg/kg, or100mg/kg
FBG
HOMA-IR

33. Effect of crocin on lipid profile in the serum of
streptozotocin-induced diabetic rats (2012)
(A) TG (Triglyceride);(B) Total cholesterol; (C) LDL-c; and (D) HDL-c. (2012)
https://www.academia.edu/30094790/Effect_of_Crocin_on_the_Insulin
_Resistance_and_Lipid_Profile_of_Streptozotocin_Induced_Diabetic_Rats
H), control group
(H+C) treated with crocin),
(D) diabetic group and
(D+C50) or (D+C100) diabetic groups treated with crocin, 50mg/kg, or100mg/kg
TG LDL
TC HDL

34. Immunoregulatory and anti-inflammatory properties of Crocus sativus
(Saffron) and its main active constituents:
A review (2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535192/

35. Synergistic effects of quercetin and crocin in the kidneys and liver of
obese Sprague-Dawley rats with Type 2 diabetes: (2021)
https://pubmed.ncbi.nlm.nih.gov/33021114/

36. ANTI-CANCER ACTIVITY OF SAFFRON

37. ANTICANCER ACTIVITY OF SAFFRON AND ITS INGREDIENTS (2014)
▪ Skin cancer
▪ Leukemia
▪ Cervical cancer
▪ Breast cancer
▪ Colorectal cancer
▪ Liver cancer
▪ Pancreatic cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996758/
Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor
and cancer preventive activities of saffron and its main ingredients on:

38. Effect of crocin on the proliferation of HCT116 cells(2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966197/#:~:text=Crocin%20reduc
ed%20the%20ratio%20of,to%20the%20STAT3%20signaling%20pathway.
(A) Proliferation of HCT116 cells treated with crocin high-dose
(271.18 µM) or low-dose (135.6 µM) for 24, 48 or 72 h.
Absorbance was recorded at 490 nm. *P<0.05, **P<0.01
vs. the control group; #P<0.05 vs. crocin high.
(B) Inhibition rate curve used for the determination of IC50 of
crocin on the proliferation of HCT116 cells. The cells were
treated with 50, 100, 200, 400, 800 or 1,600 µM crocin for
48 h before the MTT assay.
HCT116 is a human colorectal carcinoma cell line

39. Cytotoxic mechanisms of the saffron carotenoids
crocin and crocetin on cancer cell lines (2014)
https://www.researchgate.net/publication/261369581_Proposed_cytotoxic_mechani
sms_of_the_saffron_carotenoids_crocin_and_crocetin_on_cancer_cell_lines

40. Anticancer effects of crocetin(2019)
http://www.eurekaselect.com/article/91274

41. CLINICAL STUDIES

42. Reported clinical studies
▪ High blood pressure
▪ Cardiovascular disease
▪ Diabetes
▪ Metabolic syndrome
▪ Polycystic ovarian syndrome
▪ Anxiety disorder
▪ Depression
▪ Dementia/Alzheimer’s disease
▪ Attention-deficit/hyperactive disorder
▪ Premenstrual syndrome
▪ Erectile dysfunction

43. The Effect of Saffron Supplementation on Blood Pressure in Adults:
A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398601/#:~:text=Results%3A%20
Our%20results%20showed%20that,0.81%2C%20p%20%3C%200.001).

44. The effect of crocin supplementation on glycemic controlin patients
with type 2 diabetes: a pilot study(2020)
https://dmsjournal.biomedcentral.com/articles/10.1186
/s13098-020-00568-6

45. Effect of crocin on lipid profile in subjects with metabolic syndrome:
A double blind randomized clinical trial (2017)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774797/

46. Effects of crocin supplementation on fasting blood glucose and in
women with PCOS:
A randomized, double-blind, placebo-controlled trial (2022)
https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.747
4
FBG
Insulin

47. Effects of crocin supplementation on lipid profiles in women with
PCOS:
A randomized, double-blind, placebo-controlled trial (2022)
https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.7474
Cholesterol Triglyceride
LDL-C HDL-C

48. Effects of crocin supplementation on inflammatory markers in women
with PCOS:
A randomized, double-blind, placebo-controlled trial (2022)
https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.7474
iL-6
TNF-α

49. Saffron for the Management of Premenstrual Dysphoric Disorder:
A Randomized Controlled Trial (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792881/
Conclusion:
Based on the findings of this study, saffron was an efficacious herbal agent for the treatment of PMDD with minimal adverse effects.
n=40 n=40 n=40

50. NEUROPSYCHIATRIC DISORDERS

51. A Comparison of Methylphenidate (MPH) and Combined Methylphenidate with Crocus
sativus (Saffron) in the Treatment of Children and Adolescents with ADHD:
A Randomized, Double-Blind, Parallel-Group, Clinical Trial (2020)
https://brieflands.com/articles/ijpbs-108390.html

52. Saffron improved depression in patients with major depression:
A Randomized, double-blind study (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787996/
Beck Depression Inventory (DBI);
0-13 is minimal
14-19 is mild
20-28 is moderate
29-63 is severe

53. Effects of Saffron Extract Supplementation on Mood, Well-Being, and
Response to a Psychosocial Stressor in Healthy Adults:
A Randomized, Double-Blind, Parallel Group, Clinical Trial (2021)
▪ No effects were observed on the primary outcome measure.
▪ A main effect of treatment was observed for depression (p = 0.05).
https://www.frontiersin.org/articles/10.3389/fnut.2020.606124/full

54. The efficacy of Crocus sativus (Saffron) versus placebo and Fluoxetine
in treating depression:
a systematic review and meta-analysis (2019)
https://www.researchgate.net/publication/332578019_The_efficacy_of_Crocus_sati
vus_Saffron_versus_placebo_and_Fluoxetine_in_treating_depression_a_systematic_r
eview_and_meta-analysis

55. Meta-analyses of primary outcomes in depression treated with saffron
(A) improvement of depression symptoms compared with placebo;
(B) improvement of depression symptoms compared with synthetic antidepressants (2018)
https://www.researchgate.net/figure/Meta-analyses-of-primary-outcomes-A-
improvement-of-depression-symptoms-compared-with_fig2_325267863

56. Saffron for mild cognitive impairment and dementia:
a systematic review and meta-analysis of randomised clinical trials (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650148/
▪ The results of this review suggest that saffron may be beneficial to improve cognitive function in patients with MCI and AD.
▪ No evidence was found to support the effects of saffron on other types of dementia.
▪ More high-quality randomised placebo-control trials are needed to further confirm the efficacy and safety of saffron for MCI and dementia.

57. Effect of saffron on neuro-transmitters (2018)
▪ Saffron modulates neurotransmitters level such as
▪ norepinephrine
▪ dopamine
▪ serotonin
▪ GABA
▪ Probable mechanism :
▪ decreasing the activity of acetylcholine esterase and
▪ inhibiting the activity of monoamine oxidase in the brain
▪ Inhibit the reuptake of norepinephrine, dopamine and serotonin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787996/#:~:text=Saffron%20affe
cts%20neurotransmitters%20level%20such,al.%2C%202015%20%E2%96%B6). https://qbi.uq.edu.au/brain/brain-functions/what-are-neurotransmitter

58. Modulatory properties of saffron on neurotransmitters (2020)
https://www.sciencedirect.com/science/article/pii/B9780128186381000289
(Crocetin)

59. ERECTILE DYSFUNCTION

60. Effect of saffron usage on IIEF-15 scores in nocturnal penile tumescence
(NPT) test before and after soffran treatment (2009)
https://www.researchgate.net/publication/24413446_Evaluation_of_Crocus_
sativus_L_saffron_on_male_erectile_dysfunction_A_pilot_study

61. Effects of Saffron (Crocus sativus) in the treatment of erectile dysfunction:
A randomized, double-blind, placebo-controlled trial (2009)
https://www.researchgate.net/publication/24413446_

62. A systematic review and meta-analysis of clinical trials on saffron
(Crocus sativus) effectiveness and safety on
erectile dysfunction and semen parameters (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987435/

63. Quality assessment of meta-analysis of studies of Saffron (Crocus sativus L.)
and health outcomes:
a meta-research review of meta-analyses and an evidence mapping study (2021)
https://www.sciencedirect.com/science/article/abs/pii/S0944711321002427
▪ PRISMA stands for Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
▪ “Assessment of Multiple Systematic Reviews” (AMSTAR). An AMSTAR score of 8 to 11
indicates high quality, 4 to 7 a moderate quality and 0 to 3 a low quality

64. ▪ TOXICITY OF SAFFRON
▪ COMMERCIAL SAFFRON PRODUCTS
▪ CULINARY USE OF SAFFRON

65. Toxicity of saffron
▪ According to the Food and Drug Administration
(FDA), saffron is Generally Recognized as Safe (GRAS)
when used as a spice or color additive in foods.
▪ Toxicological studies have been identified that the toxicity of
saffron has been found to be quite low and oral LD50 of
saffron in animal was 20.7 g/kg administrated as a
decoction.
▪ It has been demonstrated that oral administration of saffron
extract at doses from 0.1 to 5g/kg was non-toxic in mice.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996758/

66. Commercial saffron products
Saffron Flower Saffron threads Saffron powder Saffron oil

67. Delicious saffron recipes

68. Summary
▪ Saffron is a name of Arabic origin, meaning “yellow flower.” It is called the
“spice of happiness”
▪ First cultivated in Greece, it spread to Iran where it is introduced to China,
India, Mediterranean, and Europe.
▪ For over five thousand years, Saffron has been used as a spice, coloring
agent and medicine.
▪ The bioactive compounds crocin, crocetin, picrocrocin and safranal have
multiple biological properties which are beneficial for health.
▪ Saffron and its derivatives have been tested for their therapeutic uses in
anxiety, depression, Parkinson’s disease, Alzheimer’s disease, metabolic
disorder, cardiovascular diseases and sexual dysfunction.
▪ The results of clinical studies with saffron are mixed. More research is
warranted to establish its efficacy.
▪ Meanwhile, the aroma, taste and flavor will continue to be enjoyed by
mankind for years to come.

69. ANY QUESTION?
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