Crocin and Cognitive Health
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:
- Improving memory and cognitive impairments induced by drugs, toxins, aging, Aβ, chronic stress, surgical ischemia-reperfusion, etc.
- Protecting neurons against various internal and external risk factors and suppressing brain injury, infarct, edema and neurologic deficits.
- Tightening/preserving integrity of blood-brain-barrier, reducing Aβ load and deposition in brain/hippocampus, and inhibiting hp-tau.
- 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.
- 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|
double blind RCT
|Mild-to-moderate AD||Saffron||30mg/day||Saffron significantly improved cognitive function in patients in comparison to placebo.||(2010)a5|
double blind RCT
|Saffron was as effective as donepezil assessed by ADAS-cog and CDR-SB, with less side effects in treatment of AD patients.||(2010)b6|
|Moderate-to severe AD||Memantine
|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)
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
|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
|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
|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.