Crocin and Eye Health

Age-related macular degeneration (AMD) AMD and other age-related eye diseases impact about 20 million Americans. AMD alone affects over 50% of this population and is the leading cause of vision decline and blindness. Currently, AMD is considered incurable and unpreventable. None of the current therapies improve visual acuity in patients with AMD. The lack of effective therapy has caused many patients to seek out alternatives to mitigate the risks of developing AMD and the other age-related eye diseases.

In recent years, a number of natural products have been studied for their impact on eye health. Saffron (the dry stigmas of Crocus sativus L) and in particular, its main active constituent, crocin, have been found in a number of research clinical trials to improve the conditions in patients with AMD, diabetic retinopathy, and glaucoma. 

Crocin is the most important constituent primarily responsible for the amazing health effects of saffron. As a unique water-soluble carotenoid with potent antioxidant and anti-inflammatory effects, crocin is found in saffron but not in common fruits and vegetables.  Since 2010, at least a dozen clinical studies of saffron and crocin in patients with macular diseases and glaucoma have been reported1-10. Saffron and crocin were found to improve and maintain visual acuity and functions in patients with AMD and diabetic maculopathy as well as decrease intraocular pressure in patients with glaucoma. The findings from these research reports are summarized the table below: 

Number of Patients Duration & Type of study Disease Treatment Oral dose per day Effects References
60 3 months RCT Diabetic macular edema Crocin 5mg, 15mg Crocin (15 mg/day) significantly improved best-corrected visual acuity (P=0.012), reduced central macular edema (P=0.005) and levels of HbA1c, FBS compared to the placebo group. Crocin (5mg/day) improved but not as significant. (2018)1
42 29 (+5) months, open label AMD Saffron vs. Lutein/
zeaxanthin (AREDS2)
20mg vs. 10mg/2mg Visual function remains stable in saffron treated patients while deteriorates in lutein/zeaxanthin group, suggesting saffron is more powerful in slowing down AMD than AREDS2 supplement. (2019)2
98 3 months RCT AMD Saffron 20mg Saffron significantly improved visual acuity and functions in patients with AMD, including those using AREDS2 supplements.  (2019)3
31 6 months RCT Stargardt Macular Dystrophy Saffron 20mg Saffron supplementation kept fERG amplitude and visual acuity unchanged in patients with the heredity macular disease; while placebo group got worse from baseline. (2019)4
54 3 months RCT dry AMD Saffron 50mg Saffron significantly increased visual acuity and visual function, especially contrast sensitivity, in the study. Not in control group.  (2017)5
60 6 months RCT dry or wet AMD Saffron 30mg Saffron (30mg/day) for 6 months may result in a mid-term, significant improvement in retinal function in patients with AMD. More effective for wet AMD. (2016)6
34 4 weeks treatment, 4 weeks washout RCT Glaucoma Saffron 30mg Saffron exerted an ocular hypotensive effect in primary open-angle glaucoma, intraocular pressure markedly decreased vs. control group after 3 weeks (p = 0.013) and after 4 weeks (p = 0.001). back to baseline after 4 weeks washout.  (2014)7
33 11 months RCT early AMD   Saffron 20mg After three months of saffron, mean fERG amplitude and fERG sensitivity improved significantly compared to baseline (p < 0.01). These changes were stable throughout the follow-up period.  (2013)8
29 14 months open label early AMD Saffron 20mg Saffron significantly improved retinal sensitivity; mean visual acuity by two Snellen lines vs. baseline values (0.75 to 0.9, P < 0.01) in 3 months. The improved retinal function and visual acuity kept stable over the follow-up period.  (2012)9
25 12 weeks RCT early AMD Saffron 20mg Saffron improved retinal flicker sensitivity & visual acuity (BCVA: one line) while no changes in placebo group in patients with early AMD.  (2010)10
Saffron supplementation was evaluated against Lutein + Zeaxanthin, two oil-soluble carotenoids, in a long-term (29+5 months) human study2.  Although the AREDS2 (Age-Related Eye Diseases Study 2) study led by National Eye Institute of the United States suggested that Lutein + Zeaxanthin could help reduce the risks of developing AMD, these two fat-soluble carotenoids did not show a benefit on AMD progression over the AREDS study or in the long-term study comparing them to saffron2,11. In fact, patients in the study treated with the AREDS2 protocol (Lutein/Zeaxanthin) presented a deterioration of visual acuity and retinal function while saffron treated patients kept quite a stable response over time. Saffron was also able to significantly improve visual acuity and functions in patients who remained on AREDS2 protocol (Lutein + Zeaxanthin)2,3. These results suggested that saffron could improve or stop the progression of AMD while the widely employed standard AREDS2 (Lutein + Zeaxanthin) was ineffective.  In addition to the effects on AMD, saffron was also found to significantly reduce intraocular pressure in patients with glaucoma and prevented patients with Stargardt Macular Dystrophy from further deterioration4,7

 

Similar to the effects seen with saffron supplementation, human study found that a dose of 15 mg per day of crocin could improve visual acuity and decrease central macular thickness in patients with diabetic maculopathy1. Crocin also improved vision in eyes with no central macular thickness. Additionally, crocetin, the metabolite of crocin, was shown to have a suppressive effect on myopia progression in children12. In preclinical studies, crocin was shown to be a potent and multi-target antioxidant, anti-inflammatory agent and neuroprotectant. Crocin was found to increase blood flow in the retina and choroid13, protect retinal photoreceptors against light-induced cell death, oxidative stress and inflammation14-17, and facilitate retinal function recovery18. Prophylactic crocin treatment improved visual acuity and visual contrast sensitivity function, protected retinal cells and integrity, and helped modulate the cellular function of cone19. Crocin was also found to inhibit cataract development through suppression of protein oxidation, glycation and aggregation in animal models20,21. No other natural products, including lutein and zeaxanthin, or therapeutics have shown similar protective and restorative effects on AMD and age-related eye diseases as crocin/saffron. 

These clinical findings suggest that saffron (crocin) supplementation could be a useful support for patients suffering from AMD and other age-related eye diseases. However, as with many other plant materials and because of its high value, commercial saffron can vary significantly in quality and could be frequently adulterated22. Saffron supplements are particularly confusing and filled with different extracts. Instead of extracting and concentrating the crocin from saffron, many commercial “saffron extracts” currently used in nutritional supplements are in fact “watered-down” saffron preparations produced by adding a large amounts of fiber or carrier to dilute saffron without specifying the content of crocin23.  Products with such watered-down “saffron extracts” may not provide any detectable beneficial effects as claimed24.  This has led to confusion and questions in the market. By knowing crocin is the active and most important constituent, it helps clarify and identify proper products. Look for products that offer sufficient crocin. 

Currently, Crocin Rich® is the only high purity natural crocin reviewed and granted as the New Dietary Ingredient (NDI) by FDA in the US. Crocin Rich® is a 100% soluble and fast-dissolving high purity crocin preparation. Unlike many saffron-derived ingredients with diluted and non-standardized crocin content, Crocin Rich® delivers consistent dose of crocin to support eye health. 

 

Reference:

  1. Effects of Crocin on Diabetic Maculopathy: A Placebo-Controlled Randomized Clinical Trial. Am J Ophthalmol. 2018, 190: 89-98.
  2. Saffron: A Multitask Neuroprotective Agent for Retinal Degenerative Diseases. Antioxidants. 2019, 8: 224; doi:10.3390/antiox8070224
  3. Saffron therapy for the treatment of mild/moderate age-related macular degeneration: a randomised clinical trial. Graefes Arch Clin Exp Ophthalmol. 2019, 257(1):31-40.
  4. Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy. Nutrients. 2019, 11: 2461; doi:10.3390/nu11102461
  5. The impact of saffron (Crocus sativus) supplementation on visual function in patients with dry age-related macular degeneration. Italian Journal of Medicine. 2017, 11: 196-201.
  6. Short-term Outcomes of Saffron Supplementation in Patients with Age-related Macular Degeneration: A Double-blind, Placebo-controlled, Randomized Trial. Med Hypothesis Discov Innov Ophthalmol. 2016, 5(1): 32-38.
  7. The ocular hypotensive effect of saffron extract in primary open angle glaucoma: a pilot study. BMC Complement Altern Med. 2014, 14:399. doi: 10.1186/1472-6882-14-399.
  8. Functional effect of Saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report. Journal of Translational Medicine. 2013, 11:228 http://www.translational-medicine.com/content/11/1/228
  9. A Longitudinal Follow-Up Study of Saffron Supplementation in Early Age-Related Macular Degeneration: Sustained Benefits to Central Retinal Function. Evidence-Based Complementary and Alternative Medicine. 2012, Article ID 429124, doi:10.1155/2012/429124
  10. Influence of Saffron Supplementation on Retinal Flicker Sensitivity in Early Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2010, 51: 6118–6124.
  11. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA, 2013, 309(19): 2005-2015.
  12. The Effect of Dietary Supplementation of Crocetin for Myopia Control in Children: A Randomized Clinical Trial. Clin. Med. 2019, 8, 1179; doi:10.3390/jcm8081179.
  13. Effects of Crocin Analogs on Ocular Blood Flow and Retinal Function. Journal of Ocular Pharmacology & Therapeutics. 1999, 15(2): 143-152.
  14. Protective Effect of Crocin against Blue Light– and White Light–Mediated Photoreceptor Cell Death in Bovine and Primate Retinal Primary Cell Culture. Invest Ophthalmol Vis Sci. 2006, 47: 3156–3163.
  15. Crocin protects retinal ganglion cells against H2O2-induced damage through the mitochondrial pathway and activation of NF-κB. Intl J Mol Med, 2016, 37: 225-232.
  16. Crocin protects retinal pigment epithelial cells from oxidative stress through suppression of the MAPK signaling pathway. Int J Clin Exp Med, 2016, 9(6): 11016-11022
  17. Crocin Inhibits Oxidative Stress and Pro-inflammatory Response of Microglial Cells Associated with Diabetic Retinopathy Through the Activation of PI3K/Akt Signaling Pathway. J Mol Neurosci. 2017, 61: 581–589
  18. Crocin prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway. Experimental Eye Research. 2013, 107: 44-51.
  19. Protective effect of crocin against the declining of high spatial frequency based visual performance in mice. Journal of Functional Foods, 2018, 49: 314–323.
  20. Inhibitory effect of crocin (s) on Lens α-crystallin glycation and aggregation, results in the decrease of the risk of diabetic cataract. Molecules, 2016, 21(2), 143; doi:10.3390/molecules21020143.
  21. Saffron administration prevents selenite-induced cataractogenesis. Molecular Vision, 2013, 19:1188-1197
  22. Commercial fraud in the middle ages: the case of the dissembling pepperer. Journal of Medieval History. 1982, 8(1): 63-72.
  23. Satiereal, a Crocus sativus L extract, reduces snacking and increases satiety in a randomized placebo-controlled study of mildly overweight, healthy women. Nutrition Research. 2010, 30: 305–313
  24. Effect of Multi-Ingredient Supplement Containing Satiereal, Naringin, and Vitamin D on Body Composition, Mood, and Satiety in Overweight Adults. Journal of Dietary Supplements. 2018, 15(6): 965-976.

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