Crocin and Cognitive Health

by Song Gao PhD
Cognitive impairment or brain fog is a symptom prior to or in the early stage of Alzheimer’s disease. About 5.8 million Americans age 65 and older are currently living with Alzheimer’s disease. In the absence of an effective therapy and prevention, the number of patients could grow significantly higher.

Drug development for Alzheimer’s disease has been focusing on single biomarkers, such as amyloid (Aβ) or Tau for decades. This single-target or single-mechanism approach has not resulted in a disease modifying therapy. Nonetheless, research over the years has led to a better understanding of brain functions and potential causes of Alzheimer’s disease.

In the adult human brain, neurogenesis or growth of new neurons, is limited to a few specific areas1. For this reason, if neurons die in most other parts of the brain, they cannot be replaced. Fortunately, the hippocampus, an important area responsible for memory formation and many cognitive functions, is one of the few specific areas where neurogenesis is still abundant in healthy adults. However, research has found hippocampal neurogenesis drops significantly in patients with Alzheimer’s disease2. It suggests that effective neuroprotection and improvement of hippocampal neurogenesis could play a critical role in supporting cognition and brain health.

It is now recognized that cognitive impairment and Alzheimer’s disease are caused by a combination of multiple risk factors over time that include genetic, environmental, lifestyle and health factors. Risk factors from these sources may individually or collectively induce oxidative stress, inflammation, and toxicity that would increase the levels of Aβ, Tau and pro-inflammatory cytokines that lead to loss of neurons, reduction of synaptic connections, interference of neurogenesis, decline of memory and cognitive functions and eventually Alzheimer’s disease.

Because of the multifactorial nature, a natural, multi-target approach with new and potent ingredients from dietary sources may offer promising alternative solutions for the prevention and alleviation of mild cognitive impairment and Alzheimer’ disease.

Crocin, the most important active constituent of saffron (the dry stigmas of Crocus sativus L), is found among natural ingredients having potent antioxidant, anti-inflammatory, neuroprotective and memory-enhancing effects. Clinical and preclinical studies of crocin and saffron in recent years have demonstrated that crocin is a potent and multi-target agent for many age-related health conditions with promising benefits for cognitive impairment and Alzheimer’ disease3. The effects of crocin revealed in hundreds of studies include:

  1. Improving memory and cognitive impairments induced by drugs, toxins, aging, Aβ, chronic stress, surgical ischemia-reperfusion, etc.
  2. Protecting neurons against various internal and external risk factors and suppressing brain injury, infarct, edema and neurologic deficits.
  3. Tightening/preserving integrity of blood-brain-barrier, reducing Aβ load and deposition in brain/hippocampus, and inhibiting hp-tau.
  4. Enhancing gene expression and protein levels of neurotrophic factors including Brain-Derived Neurotrophic Factor (BDNF) and cAMP Responsive Element Binding Protein (CREB) that are essential for neurogenesis, neural development, cell survival, axonal growth, adaptation, and synaptic plasticity.
  5. Reducing AD associated health risk factors including diabetes, cardiovascular disease (CVD), multiple sclerosis, stroke, depression, etc.

Crocin is believed to be primarily responsible for the effects of saffron. At least 8 human clinical studies reported saffron or its combinations with other natural ingredients significantly improved scores on Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) or Mini mental state examination (MMSE) in patients with mild-moderate, moderate-severe Alzheimer’s disease, vascular dementia (VaD) and major neurocognitive disorders. Signs of enhanced hippocampal neurogenesis or growth of neuron are likely observed by MRI in patients with mild cognitive impairment (MCI) after one year use of saffron. The four clinical studies with saffron alone were summarized in Table 1 below:

Table 1. Clinical studies of saffron in patients with MCI and AD

Number of Patients Duration & Type of study Disease Treatment Oral dose per day Effects References
35 12 months single blind Mild cognitive impairment (MCI) Saffron 125mg/day Saffron significantly improved cognitive impairment MMSE (P=0.015), specific domains (vMRI), brain activation by EEG (P300), while the control group deteriorated in all assessments.  (2016)4
46 16 weeks
double blind RCT		 Mild-to-moderate AD Saffron 30mg/day Saffron significantly improved cognitive function in patients in comparison to placebo. (2010)a5
54 22 weeks
double blind RCT		 Mild-to-moderate AD Donepezil
Saffron		 10mg/day
30mg/day		 Saffron was as effective as donepezil assessed by ADAS-cog and CDR-SB, with less side effects in treatment of AD patients. (2010)b6
68 12 months
double blind		 Moderate-to severe AD Memantine
Saffron (crocin)		 20mg/day
30mg/day (3.3-3.5mg/day)		 Saffron exhibited similar efficacy to memantine in prevention of cognitive decline (SCIRS, FAST) with a favorable safety profile. (2014)7


Lately, crocin has been clinically evaluated lately and shown potent and multi-target effects in improving health conditions, some of which are considered to be risk factors of Alzheimer’s disease. Clinical studies to confirm the effects of crocin on cognitive health and Alzheimer’s disease could be expected in the near future.

In the past five years, at least a dozen clinical studies reported crocin (15-30mg/day) significantly improved quality of life and conditions in patients with diseases including Type II diabetes, heart disease, acute ischemic stroke, multiple sclerosis, depression, and sleep disorders. Tablet 2 summarized these clinical studies.

Table 2. Clinical Studies of Crocin (2015-2020)

No. of
Subjects		 Duration &
Type of study		 Disease Treatment Oral dose per day Effects References
40 16 weeks RCT  Osteoarthritis Crocin               placebo 15mg Crocin significantly reduced pain assessed by VAS pain score and markedly improved OA through anti-inflammatory and immunoregulatory effects, shown improved levels of IL-17, C-reactive protein, and T cells. (2020)8
50 12 weeks RCT  Type II Diabetes Crocin               placebo 2x15mg In patients with T2D, crocin led to significant improvements in plasma levels of glucose, insulin, and hemoglobin A1c, systolic blood pressure, insulin resistance and insulin sensitivity. (2020)9
84 8 weeks RCT Coronary artery disease (CAD) Crocin, or saffron extract, or placebo 2x15mg; 2x15mg Crocin provides beneficial effects on CAD patients by increasing the gene expression of SIRT1 and AMPK and decreasing the expression of LOX1 and NF-κB. (2019)10
39 3 months rd/db Acute ischemic stroke Saffron extract (20% crocin) 200mg 1st 4 days; then 100mg of 3 months High crocin saffron extract significantly improved severity of stroke in the first 4 days and 3 months. Markedly reduced levels of NSE, S100 vs control, and increased BDNF level in 4th day. (2019)11
40 4 weeks RCT
controlled		 Multiple sclerosis Crocin               placebo 2x15mg Crocin provided beneficial and therapeutic effects by significantly reducing DNA damage, inflammation, and oxidative stress.  (2019)12
50 8 weeks RCT Under Methadone maintenance treatment Crocin               placebo 2x15mg Crocin significantly improved depression, anxiety, general health & sleep quality in patients under MMT vs. the placebo.  (2019)13
47 11 weeks RCT Burning mouth syndrome Crocin               citalopram 2x15mg
20mg		 Crocin treatment significantly reduced severity of burning, depression and anxiety. No difference vs citalopram.  (2019)14
60 12 weeks RCT Diabetic maculopathy Crocin               placebo 5mg, 15mg Crocin significantly improved the best-corrected visual acuity, central macular thickness, fasting blood sugar and glycated hemoglobin A1c (2018)15
58 8 weeks RCT coronary artery disease (CAD) Crocin, or saffron extract (SAE) 2x15mg 2x15mg Crocin and SAE could improve depression and health-related quality of life in patients with CAD. (2017)16
33 8 weeks RCT Depression in patients with metabolic syndrome Crocin               placebo 2x15mg Degree of depression in BDI decreased significantly in the crocin group and the difference between the 2 groups was statistically significant (p = 0.013). (2016)17
60 8 weeks RCT metabolic
syndrome		 Crocin 2x15mg Crocin resulted in significant reduction (11.7%) in serum Prooxidant-Antioxidant Balance concentrations. (2016)18
40 4 weeks RCT major depressive disorder  Crocin + fluoxetine, or sertraline, or citalopram 30mg + 20mg/f, or 50mg/s, or 20mg/c Crocin group showed significantly improved scores on BDI, BAI and GHQ (17.6,12.7 and 17.2 vs. 6.15, 2.6 and 10.3 in placebo group, respectively) (2015)19


As with many other plant materials and because of its high value - a pound of authentic saffron can cost $2,000 to $10,000, commercial saffron varies significantly in quality and could be frequently adulterated20. 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 amount of fiber or carrier to dilute saffron without specifying the content of crocin21.  Products with such watered-down “saffron extracts” are not comparable to saffron and may not provide any detectable beneficial effects as claimed22.  This has created confusion and questions in the market.

By knowing crocin is the key constituent of saffron, it helps clarify and identify proper products. Crocin Rich® is the only FDA reviewed and approved crocin New Dietary Ingredient in the USA. Unlike many other saffron-derived ingredients with diluted and non-standardized crocin content, Crocin Rich® delivers a consistent dose of crocin. Supplements formulated with Crocin Rich® and other natural antioxidants could could be a powerful, multi-target and synergistic means to support cognitive health and quality of life.

To get above mentioned beneficial effects, it is recommended to use supplements with enough purified or standardized crocin.

Like many age-related health conditions, prevention is the best medicine. Take Action Now.

For a related article about Crocin and Eye Health click here

Reference

  • Tobin MK, et al. (2019), Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer’s Disease Patients. Cell Stem Cell, 2019, 24: 974–982.
  • Moreno-Jiménez EP, et al. (2019) Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature Medicine, 2019, 25: 554-560.
  • Finley JW & Gao S. (2017) Perspective on Crocus sativus L. (Saffron) Constituent Crocin: A Potent Water-Soluble Antioxidant and Potential Therapy for Alzheimer’s Disease. Food Chem. 2017, 65, 1005−1020.
  • Tsolaki M, et al. (2016) Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. Journal of Alzheimer’s Disease. 2016, 54: 129–133.
  • Akhondzadeh S, et al. (2010) Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16-week, randomized and placebo-controlled trial. J of Clin Pharm and Ther. 2010, 35: 581–588.
  • Akhondzadeh S, et al. (2010) A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of -to-moderate Alzheimer’s disease. Psychopharmacology. 2010, 207: 637–643.
  • Farokhnia M, et al. (2014) Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer’s disease: a double-blind randomized clinical trial. Psychopharmacol Clin Exp 2014; 29: 351–359.
  • Poursamimi J, et al. (2020) Immunoregulatory Effects of Krocina™, a Herbal Medicine Made of Crocin, on Osteoarthritis Patients: A Successful Clinical Trial in Iran. Iran J Allergy Asthma Immunol. 2020; 19(3): 253-263.
  • Behrouz V, et al. (2020) The efect of crocin supplementation on glycemic control, insulin resistance and active AMPK levels in patients with type 2 diabetes: a pilot study. Diabetol Metab Syndr. 2020, 12:59. https://doi.org/10.1186/s13098-020-00568-6.
  • Abedimanesh N, et al. (2020) Effects of crocin and saffron aqueous extract on gene expression of SIRT1, AMPK, LOX1, NF-κB, and MCP-1 in patients with coronary artery disease: A randomized placebo-controlled clinical trial. Phytother Res. 2020, 34(5): 1114-1122.
  • Asadollahi M, et al. (2019) Protective properties of the aqueous extract of saffron (Crocus sativus L.) in ischemic stroke, randomized clinical trial. J Ethnopharm. 2019, 238, https://doi.org/10.1016/j.jep.2019.111833
  • Ghiasian M, et al. (2019) Effects of crocin in reducing DNA damage, inflammation, and oxidative stress in multiple sclerosis patients: A double‐blind, randomized, and placebo‐controlled trial. J Biochem Mol Toxi. 2019, 33(12), e22410.
  • Khalatbari-mohseni A, et al (2019) The effects of crocin on psychological parameters in patients under methadone maintenance treatment: a randomized clinical trial. Subst Abuse Treat Prev Policy. 2019; 14: 9. doi: 10.1186/s13011-019-0198-1
  • Pakfetrat A, et al (2019) Evaluation of the effectiveness of crocin isolated from saffron in treatment of burning mouth syndrome: A randomized controlled trial. Avicenna J Phytomed, 2019; 9(6): 505-516.
  • Sepahi et al. (2018) Effects of Crocin on Diabetic Maculopathy: A Placebo-Controlled Randomized Clinical Trial. Am J Ophthalmol. 2018, 190: 89-98.
  • Abedimanesh N et al. (2017) Effects of Saffron Aqueous Extract and Its Main Constituent, Crocin, on Health-Related Quality of Life, Depression, and Sexual Desire in Coronary Artery Disease Patients: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Iran Red Crescent Med J. 2017, 19(9): e13676. doi: 10.5812/ircmj.13676.
  • Nikbakht-Jam I, et al. (2017) The effects of crocin on the symptoms of depression in subjects with metabolic syndrome. Adv Clin Exp Med. 2017, 26(6): 925–930.
  • Nikbakht-Jam I, et al (2016) Effect of crocin extracted from saffron on pro-oxidant–anti-oxidant balance in subjects with metabolic syndrome: A randomized, placebo-controlled clinical trial. Eur J Interg Med. 2016, 8(3): 307-312.
  • Talaei A, et al (2015) Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: A randomized, double-blind, placebo-controlled, pilot clinical trial. Journal of Affective Disorders. 2015, 174: 51–56.
  • Reyerson KL. Commercial fraud in the middle ages: the case of the dissembling pepperer. Journal of Medieval History. 1982, 8(1): 63-72.
  • Gout B, et al. (2010) 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
  • Gonzalez AM, et al. (2018) 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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