Crocetin

• Antioxidant protection
• Anti-inflammatory effects
• Neuroprotection
• Cardiovascular support

• Vision health
• Cognitive function
• Mood regulation
• Metabolic health
• Sleep quality improvement
• Liver protection

Crocetin, a natural carotenoid dicarboxylic acid found in saffron (Crocus sativus L.), exerts its biological effects through multiple molecular pathways. As a potent antioxidant, crocetin directly neutralizes reactive oxygen species (ROS) and free radicals, preventing oxidative damage to cellular components. It enhances the activity of endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), strengthening cellular defense mechanisms. Crocetin’s anti-inflammatory properties stem from its ability to inhibit pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6).

It suppresses nuclear factor-kappa B (NF-κB) signaling, a master regulator of inflammatory responses, and inhibits cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. In the cardiovascular system, crocetin improves endothelial function by enhancing nitric oxide (NO) production and bioavailability, promoting vasodilation and improving blood flow. It inhibits platelet aggregation, reducing thrombosis risk, and modulates lipid metabolism by inhibiting pancreatic lipase activity and enhancing cholesterol efflux. Crocetin crosses the blood-brain barrier and exerts neuroprotective effects by reducing amyloid-beta aggregation, inhibiting tau hyperphosphorylation, and protecting neurons from excitotoxicity.

It enhances brain-derived neurotrophic factor (BDNF) expression, supporting neuronal survival and plasticity. Crocetin modulates neurotransmitter systems, particularly serotonin, dopamine, and gamma-aminobutyric acid (GABA), which may explain its effects on mood and cognition. In metabolic regulation, crocetin enhances insulin sensitivity by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and AMP-activated protein kinase (AMPK) pathways. It improves glucose uptake in peripheral tissues and protects pancreatic beta cells from oxidative stress.

Crocetin also demonstrates anti-cancer properties by inducing apoptosis in cancer cells, inhibiting cell proliferation, and suppressing angiogenesis through downregulation of vascular endothelial growth factor (VEGF). It inhibits matrix metalloproteinases (MMPs), potentially reducing cancer cell invasion and metastasis. For vision health, crocetin protects retinal cells from light-induced damage, reduces oxidative stress in the eye, and improves retinal blood flow. It may also enhance rhodopsin regeneration, supporting visual function in low-light conditions.

Additionally, crocetin has shown hepatoprotective effects by enhancing liver detoxification enzymes, reducing lipid peroxidation in hepatocytes, and improving bile flow. Recent research suggests crocetin may influence circadian rhythm regulation through modulation of clock genes, potentially explaining its effects on sleep quality.

The optimal dosage of crocetin is typically 7.5-30 mg per day, often taken in divided doses. When consumed as part of saffron extract, a dose containing 30-100 mg of saffron standardized to contain 2-3% crocetin or crocin is commonly used.

Crocetin has moderate bioavailability (approximately 30-40%) when taken orally. It is more bioavailable than its glycosylated precursor, crocin, which must be hydrolyzed to crocetin in the intestinal tract before absorption. Crocetin is rapidly absorbed in the intestine, with peak plasma concentrations typically reached within 1-2 hours after ingestion.

Consumption with fatty meals or oils increases absorption due to crocetin’s lipophilic nature, Liposomal formulations can increase bioavailability by 2-3 times, Nano-emulsified forms improve dissolution and absorption, Phospholipid complexes enhance membrane permeability and absorption, Piperine (black pepper extract) may inhibit glucuronidation and increase bioavailability, Formulations with cyclodextrins improve water solubility and absorption

Crocetin is best taken with meals, particularly those containing some fat, to enhance absorption. For cognitive benefits, morning dosing is often recommended. For sleep benefits, taking crocetin 1-2 hours before bedtime may be optimal. Dividing the daily dose into two administrations (morning and evening) may provide more consistent blood levels for certain therapeutic applications.

Absorption may be reduced when taken concurrently with high-fiber foods or supplements. Allow at least 2 hours between crocetin and medications that require optimal absorption for efficacy.

• Nausea (rare, <3% of users)
• Headache (rare, <2% of users)
• Dizziness (rare, <2% of users)
• Dry mouth (rare, <2% of users)
• Digestive discomfort (rare, <3% of users)
• Allergic reactions (very rare, primarily in individuals with known allergy to plants in the Iridaceae family)
• Changes in appetite (rare, <1% of users)
• Drowsiness (uncommon, primarily at higher doses)

• Pregnancy and breastfeeding (insufficient safety data)
• Known allergy to saffron or plants in the Iridaceae family
• Bipolar disorder (may potentially trigger manic episodes at high doses)
• Bleeding disorders (theoretical risk due to antiplatelet effects)
• Hypotension (may enhance blood pressure-lowering effects)
• Scheduled surgery (discontinue 2 weeks before due to potential antiplatelet effects)

• Anticoagulant and antiplatelet medications (may enhance blood-thinning effects)
• Antihypertensive medications (may potentiate blood pressure-lowering effects)
• Antidepressants (potential additive effects, particularly with SSRIs and MAOIs)
• Sedatives and hypnotics (may enhance sedative effects)
• Medications metabolized by cytochrome P450 enzymes (potential for mild interactions, though clinical significance is unclear)
• Immunosuppressants (theoretical interaction based on immunomodulatory effects)

The upper tolerable limit for crocetin has not been definitively established. However, doses up to 50 mg per day have been used in short-term clinical studies without serious adverse effects. For long-term use, staying within the 7.5-30 mg daily range is recommended. When consumed as saffron extract, upper limits of 1.5 g of saffron per day should not be exceeded, as higher doses may have toxic effects.

Crocetin does not have FDA approval as a drug. It is generally classified as a dietary supplement ingredient in the United States under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As a supplement ingredient, it can be marketed without pre-approval, but manufacturers cannot make specific disease treatment claims. Saffron extract, which contains crocetin, is Generally Recognized as Safe (GRAS) as a food ingredient and flavoring agent.

Eu: In the European Union, crocetin is not approved as a medicine but may be sold as a food supplement. The European Food Safety Authority (EFSA) has not approved any health claims for crocetin or saffron extract. Saffron extract is approved as a food coloring (E164) and flavoring agent.

Canada: Health Canada allows crocetin as a natural health product (NHP) ingredient. It is listed in the Natural Health Products Ingredients Database with approved uses for antioxidant support and mood support. Products containing crocetin must have a Natural Product Number (NPN) to be legally sold in Canada.

Australia: The Therapeutic Goods Administration (TGA) classifies crocetin-containing products as complementary medicines. Saffron extract is listed in the Australian Register of Therapeutic Goods (ARTG) with permitted indications for antioxidant activity and mood support.

Japan: In Japan, crocetin has received approval as a ‘Food for Specified Health Uses’ (FOSHU) for improving sleep quality and reducing eye fatigue. It has undergone significant clinical testing in Japan and is widely used in functional foods and supplements.

China: The China Food and Drug Administration (CFDA) permits crocetin in traditional Chinese medicine formulations and as a food supplement ingredient. Saffron is listed in the Chinese Pharmacopoeia with recognized medicinal properties.

India: The Ayurvedic Pharmacopoeia of India recognizes saffron (containing crocetin) as a medicinal herb. The Food Safety and Standards Authority of India (FSSAI) permits its use in supplements and traditional formulations.

High

Crocetin supplements typically range from $1.00 to $3.50 per effective daily dose (15-30 mg). Saffron extracts standardized for crocetin content generally cost $0.80 to $2.50 per day at effective doses. Pure isolated crocetin is significantly more expensive than saffron extract products.

Crocetin represents a relatively high-cost supplement compared to many other antioxidants and anti-inflammatory compounds. The high cost is primarily due to the labor-intensive harvesting process for saffron and the low yield of active compounds from the raw material. Despite the high cost, crocetin may offer good value for specific applications where alternatives are limited or less effective. For cognitive and mood benefits, the cost-effectiveness is moderate when compared to pharmaceutical alternatives, which are often more expensive and may have more side effects.

For vision health, crocetin offers unique benefits that may justify the cost for individuals with specific eye conditions or age-related vision concerns. The development of enhanced bioavailability formulations has improved cost-efficiency by allowing lower effective doses. Synthetic crocetin, while still expensive, may eventually provide a more cost-effective alternative as production methods improve. For general antioxidant support, other less expensive options (such as vitamin C, vitamin E, or quercetin) may offer better value unless the specific mechanisms of crocetin are desired.

When evaluating cost-efficiency, it’s important to consider that many commercial products contain saffron extract with variable and sometimes low crocetin content – products standardized to contain specific amounts of crocetin or crocin typically offer better value despite higher upfront costs.

Pure crocetin has a shelf life of approximately 18-24 months when properly stored. Formulated products typically have a shelf life of 12-36 months, depending on the specific formulation, packaging, and storage conditions.

Store in airtight, opaque containers away from direct light, heat, and moisture. Refrigeration (2-8°C) is recommended for pure crocetin and some formulations to extend shelf life. Avoid freezing unless specifically recommended by the manufacturer. Once opened, products should ideally be used within 6 months for maximum potency. Blister-packed capsules or tablets maintain stability longer than bulk containers that are frequently opened.

Exposure to light (especially UV light) – causes isomerization and breakdown of the polyene chain, Oxidation – crocetin’s conjugated double bond system is susceptible to oxidative degradation, Heat – accelerates degradation reactions, with significant losses at temperatures above 40°C, Moisture – can promote hydrolysis and microbial growth, pH extremes – crocetin is most stable at slightly acidic to neutral pH (5-7), Metal ions (especially iron and copper) – catalyze oxidative degradation, Enzymatic degradation – certain oxidases can break down carotenoid structures, Interaction with other supplement ingredients – particularly oxidizing agents or acidic compounds

Synthesis Methods

Natural Sources

Quality Considerations

Crocetin, as a component of saffron (Crocus sativus L.), has a rich historical usage dating back thousands of years across multiple civilizations. In ancient Persia (modern-day Iran), saffron was used medicinally as early as 2300 BCE for treating melancholy (depression), inflammation, and pain. Ancient Egyptian medical papyri mention saffron as a remedy for gastrointestinal ailments and as a mood enhancer. The compound was highly valued in ancient Greece and Rome, where Hippocrates and Galen recommended it for treating insomnia, pain, and melancholy.

In traditional Chinese medicine, saffron (known as ‘Fan Hong Hua’) has been used for over 2,000 years to stimulate blood circulation, reduce pain, and treat depression and menstrual disorders. Ayurvedic medicine in India has employed saffron for centuries as a ‘rasayana’ (rejuvenative) to promote longevity, enhance cognition, and treat respiratory conditions. In medieval Europe, saffron was used to combat the Black Death and other epidemics due to its perceived protective properties. Traditional Persian medicine specifically recognized saffron’s benefits for vision, describing its use for strengthening eyesight and treating various ocular conditions.

In traditional Arabic medicine, saffron was prescribed for cardiovascular health and as an aphrodisiac. Throughout history, saffron has also been used as a culinary spice and natural dye, with its medicinal properties often intertwined with cultural and culinary applications. While historical uses specifically attributed to crocetin (rather than whole saffron) are limited due to the lack of analytical capabilities in ancient times, modern research has confirmed that many of the traditional benefits associated with saffron are indeed linked to its crocetin content. The historical use of saffron across diverse medical traditions and its consistent application for mood, cognitive, and cardiovascular conditions aligns remarkably well with modern scientific understanding of crocetin’s mechanisms of action.

Hausenblas HA, Saha D, Dubyak PJ, Anton SD. Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials. Journal of Integrative Medicine. 2013;11(6):377-383., Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human Psychopharmacology. 2014;29(6):517-527.

Effects of Crocetin Supplementation on Cognitive Function in Older Adults with Subjective Memory Complaints (ClinicalTrials.gov Identifier: NCT04014192), Evaluation of Crocetin on Retinal Blood Flow in Patients with Diabetic Retinopathy (ClinicalTrials.gov Identifier: NCT03789695), Crocetin for Management of Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Trial (ISRCTN Registry: ISRCTN15416797)