Safranal

• Antioxidant
• Neuroprotective
• Anti-inflammatory

• Anxiolytic
• Hypnotic
• Anticonvulsant
• Antidepressant
• Cardioprotective
• Hepatoprotective
• Nephroprotective
• Antinociceptive

Safranal, a monoterpene aldehyde and the main component responsible for saffron’s distinctive aroma, exerts its biological effects through multiple mechanisms. As an antioxidant, safranal effectively scavenges free radicals and reactive oxygen species (ROS), particularly hydroxyl radicals and superoxide anions. It enhances the activity of endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase, while simultaneously increasing glutathione levels in tissues. This antioxidant activity contributes significantly to safranal’s protective effects against oxidative damage in various tissues, particularly in the brain, heart, liver, and kidneys.

In the central nervous system, safranal exhibits neuroprotective properties through several pathways. It modulates the GABAergic system by enhancing GABA receptor function, which contributes to its anxiolytic, hypnotic, and anticonvulsant effects. Studies have shown that safranal can inhibit pentylenetetrazol (PTZ)-induced seizures by interacting with GABA receptors and potentially through opioid receptors. Safranal also demonstrates neuroprotective effects by reducing glutamate excitotoxicity.

It decreases extracellular levels of excitatory amino acids like glutamate and aspartate during neurotoxic insults, thereby preventing excessive neuronal excitation and subsequent cell death. This mechanism is particularly relevant in conditions like epilepsy, ischemic brain injury, and neurodegenerative disorders. The antidepressant effects of safranal appear to be mediated through monoaminergic mechanisms, including inhibition of monoamine oxidase and modulation of serotonin, dopamine, and norepinephrine levels in the brain. Safranal may also influence the hypothalamic-pituitary-adrenal (HPA) axis, which plays a crucial role in stress responses and mood regulation.

Safranal’s anti-inflammatory properties involve inhibition of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). It suppresses the nuclear factor-kappa B (NF-κB) signaling pathway, a master regulator of inflammatory responses, by preventing the phosphorylation and degradation of inhibitory κB (IκB). Additionally, safranal inhibits cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), thereby reducing the production of inflammatory mediators like prostaglandins and nitric oxide. In the cardiovascular system, safranal exhibits cardioprotective effects through multiple mechanisms.

It improves endothelial function by enhancing nitric oxide (NO) production via increased endothelial nitric oxide synthase (eNOS) phosphorylation. Safranal also activates the Akt/GSK-3β/eNOS pathway, which is crucial for myocardial protection against ischemia-reperfusion injury. Its hypotensive effects are attributed to vasodilatory properties, potentially through calcium channel modulation and interaction with β2-adrenoceptors. Safranal’s hepatoprotective and nephroprotective effects are primarily attributed to its antioxidant and anti-inflammatory properties.

It prevents lipid peroxidation in liver and kidney tissues, reduces inflammatory responses, and enhances tissue regeneration following toxic insults. In metabolic regulation, safranal has shown potential in improving glucose homeostasis. It may enhance insulin sensitivity and protect pancreatic β-cells from oxidative damage, contributing to its anti-diabetic effects. The antinociceptive (pain-relieving) effects of safranal involve both central and peripheral mechanisms.

Centrally, it may interact with opioid receptors and modulate descending pain pathways. Peripherally, its anti-inflammatory properties contribute to reduced pain sensation by inhibiting inflammatory mediators at the site of injury. At the molecular level, safranal interacts with DNA and proteins, potentially influencing gene expression and protein function. It has been shown to bind to DNA, particularly in GC-rich regions, and can interact with proteins like human serum albumin, which may affect its bioavailability and distribution in the body.

The optimal dosage of safranal is not definitively established due to limited human clinical trials using isolated safranal. Most studies have used saffron extract standardized to contain specific amounts of safranal. Based on available research, effective doses of pure safranal range from 0.1-1 ml/kg in animal studies, which would translate to approximately 0.5-5 mg/kg in humans using allometric scaling. When consumed as part of saffron extract, products standardized to contain 0.3-0.5% safranal at doses of 30 mg daily (providing approximately 0.09-0.15 mg of safranal) have shown therapeutic effects.

For specific conditions, dosages may vary, and it’s generally recommended to start at the lower end of the dosage range and adjust as needed under healthcare provider supervision.

Safranal has moderate oral bioavailability (approximately 30-40%) due to its lipophilic nature and relatively small molecular size, which facilitate passive diffusion across intestinal membranes. As a volatile compound, safranal can also be absorbed through the respiratory tract when inhaled, providing an alternative route of administration. Pharmacokinetic studies indicate that safranal reaches peak plasma concentrations (Tmax) within 30-60 minutes after oral administration, with a half-life of approximately 4-6 hours. The distribution volume is relatively large, suggesting extensive tissue distribution, particularly to lipid-rich tissues including the brain, which explains its pronounced neuropsychological effects.

Safranal readily crosses the blood-brain barrier due to its lipophilic properties, allowing it to exert direct effects on central nervous system function. Metabolism of safranal primarily occurs in the liver through oxidation of the aldehyde group to carboxylic acid, followed by conjugation with glucuronic acid or glycine for excretion. Some portion of safranal may also undergo reduction to the corresponding alcohol. Excretion is mainly via the kidneys, with some elimination through the lungs due to its volatile nature.

Liposomal formulations can increase safranal bioavailability by 2-3 fold by enhancing intestinal absorption and protecting it from premature metabolism, Nanoparticle delivery systems, particularly those using biodegradable polymers like PLGA, can improve bioavailability by up to 3-fold compared to standard formulations, Cyclodextrin inclusion complexes improve safranal stability and solubility, potentially increasing bioavailability by 50-70%, Oil-based formulations or taking safranal with a fatty meal can increase absorption by 30-40% by enhancing solubility and lymphatic transport, Co-administration with piperine (from black pepper) may inhibit hepatic enzymes involved in safranal metabolism, potentially increasing bioavailability by 20-30%, Microemulsion formulations can enhance both solubility and permeability, improving bioavailability by 2-3 fold, Inhalation delivery systems can bypass first-pass metabolism, providing more direct access to the bloodstream and brain

For optimal absorption, safranal supplements are best taken with meals, particularly those containing some healthy fats. This approach enhances the solubilization and absorption of safranal due to its lipophilic nature. For anxiety and stress management, taking safranal in the morning may provide day-long anxiolytic effects without excessive sedation. For sleep enhancement, administration approximately 30-60 minutes before bedtime is recommended to align with its peak plasma concentration at the desired sleep onset time.

When used for seizure management, dividing the daily dose into 2-3 administrations helps maintain more consistent blood levels throughout the day. For neuroprotective effects, consistent daily timing is more important than specific time of day, with morning administration often preferred for compliance reasons. For pain management, taking safranal approximately 30 minutes before anticipated pain triggers or at the first sign of pain may provide the most effective relief. When used for cardiovascular protection, morning administration may be optimal to align with natural circadian rhythms of cardiovascular function.

• Sedation and drowsiness (reported in 5-10% of users, dose-dependent)
• Dry mouth (reported in 3-5% of users)
• Dizziness (reported in 2-4% of users)
• Headache (reported in 1-3% of users)
• Nausea (reported in 1-2% of users)
• Changes in appetite (reported in 1-2% of users)
• Mild anxiety or nervousness at low doses (reported in <1% of users)
• Allergic reactions (rare, <0.5% of users)
• Hypotension, especially at higher doses (reported in 1-2% of users)

• Pregnancy (due to potential uterine-stimulating effects)
• Breastfeeding (insufficient safety data)
• Bipolar disorder (may potentially trigger manic episodes when used as an antidepressant)
• Hypotension (low blood pressure) as safranal has hypotensive effects
• Bleeding disorders (safranal may have mild anticoagulant properties)
• Scheduled surgery (discontinue at least 2 weeks before due to potential effects on blood clotting)
• Known allergy to saffron or plants in the Iridaceae family
• Children under 12 years (insufficient safety data)
• Severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)

• Sedatives and CNS depressants (including benzodiazepines, barbiturates, opioids) – safranal may enhance sedative effects
• Antidepressants (SSRIs, SNRIs, MAOIs) – potential for serotonin syndrome when combined with safranal
• Anticonvulsants – safranal may enhance or interfere with anticonvulsant medications
• Anticoagulants and antiplatelet drugs (e.g., warfarin, aspirin) – safranal may enhance blood-thinning effects
• Antihypertensive medications – safranal may potentiate blood pressure-lowering effects
• Medications metabolized by cytochrome P450 enzymes – potential for altered drug metabolism
• Medications affecting GABA receptors – safranal may enhance or interfere with their effects
• Hypoglycemic medications – safranal may enhance blood glucose-lowering effects

The therapeutic index of safranal appears to be narrower than other active constituents in saffron stigma, such as crocin. In animal studies, doses above 1.5 ml/kg have shown toxicity, suggesting an upper limit of approximately 0.75-1 ml/kg in humans using allometric scaling. For pure safranal, a conservative upper limit of 5 mg/kg per day is suggested based on available toxicity data. When consumed as part of saffron extract, the upper limit would correspond to approximately 100 mg of extract standardized to contain 0.5% safranal (providing 0.5 mg of safranal) per day.

Acute toxicity studies in animals have shown that the LD50 (lethal dose for 50% of the population) for safranal is approximately 1.48 ml/kg in mice, indicating a moderate toxicity potential. Chronic toxicity studies are limited, but available data suggest that long-term use at therapeutic doses does not produce significant adverse effects on major organ systems. However, due to its potential sedative and hypotensive effects, caution is advised when using safranal at higher doses, particularly in individuals with pre-existing cardiovascular conditions or those taking medications with similar effects.

In the United States, safranal as an isolated compound does not have a specific regulatory status. However, its primary source, saffron, is classified as Generally Recognized as Safe (GRAS) for use as a flavoring agent and colorant (21 CFR 182.10, 182.20). As a component of dietary supplements, safranal falls under the Dietary Supplement Health and Education Act (DSHEA) of 1994, which means it can be marketed without FDA pre-approval but cannot make specific disease treatment claims. Saffron, which contains safranal, is included in the FDA’s list of ‘Old Dietary Ingredients’ that were marketed prior to October 15, 1994.

Pure safranal as a single ingredient supplement would likely require a New Dietary Ingredient (NDI) notification to the FDA before marketing, as it was not commonly used in supplement form before 1994. The FDA has not established specific safety guidelines or upper limits for safranal consumption.

In the European Union, safranal derived from saffron is recognized as a natural flavoring substance. The European Food Safety Authority (EFSA) recognizes saffron extracts containing safranal as traditional food ingredients. For medicinal purposes, saffron preparations containing safranal may be regulated under the Traditional Herbal Medicinal Products Directive (2004/24/EC) in some EU countries. The European Medicines Agency (EMA) has not yet issued a specific monograph for safranal or saffron, though they are included in several national pharmacopoeias within Europe.

Pure safranal as a novel food ingredient would require authorization under the Novel Food Regulation (EU) 2015/2283. The EFSA has not established specific safety guidelines or upper limits for safranal consumption.

In Iran, the world’s largest producer of saffron, safranal is recognized as an active component of saffron and is regulated as both a food ingredient and a traditional medicine by the Iranian Food and Drug Administration. In Japan, safranal is recognized as a natural flavoring agent and is regulated accordingly. In China, saffron is listed in the Chinese Pharmacopoeia, with safranal recognized as an active component. Safranal is used as an analytical marker for quality control of saffron in traditional Chinese medicine.

In India, saffron containing safranal is recognized in the Ayurvedic Pharmacopoeia as a traditional medicinal ingredient and is regulated by the Ministry of AYUSH. Australia’s Therapeutic Goods Administration (TGA) includes saffron in the list of substances that may be used in listed medicines, with safranal being recognized as an active component. In Canada, saffron is listed in the Natural Health Products Ingredients Database (NHPID), with safranal acknowledged as an active constituent.

May help support a healthy mood (structure/function claim allowed in the US for supplements containing safranal), May help promote relaxation (structure/function claim allowed in the US), May help support normal sleep patterns (structure/function claim allowed in the US), Traditionally used to support emotional well-being (allowed in some EU countries under traditional herbal registration), Contributes to normal psychological function (pending EFSA evaluation), Traditionally used to promote relaxation and sleep (allowed in some EU countries under traditional herbal registration)

Cannot claim to treat, cure, or prevent anxiety disorders (all jurisdictions), Cannot claim to treat, cure, or prevent depression (all jurisdictions), Cannot claim to treat, cure, or prevent insomnia or sleep disorders (all jurisdictions), Cannot claim to treat, cure, or prevent seizure disorders or epilepsy (all jurisdictions), Cannot claim to treat, cure, or prevent neurodegenerative diseases (all jurisdictions), Cannot claim to treat, cure, or prevent cardiovascular diseases (all jurisdictions), Cannot make claims regarding treatment of pain disorders without approved clinical trials (all jurisdictions), Cannot make claims regarding specific therapeutic effects without adequate substantiation (all jurisdictions)

Pure Safranal: $300-800 per gram for analytical grade (>85% purity)

Standardized Saffron Extract: $20-40 for 30 capsules (standardized to contain 0.3-0.5% safranal)

Saffron Essential Oil: $50-150 per 5 ml (containing 60-70% safranal)

Saffron Stigmas: $5-15 per gram ($5,000-15,000 per kilogram)

1

Pure safranal prices have remained high due to complex extraction processes and limited commercial production. The cost of saffron, the primary source of safranal, has been increasing gradually over the past decade due to labor-intensive harvesting methods and growing global demand. Climate change affecting growing regions in Iran, Spain, and Kashmir may further impact saffron prices and consequently safranal availability in the coming years. The volatile nature of safranal makes it challenging to extract and stabilize, contributing to its high cost.

Advances in extraction technology and increasing commercial interest in safranal have led to some economies of scale, but prices remain high compared to many other natural compounds. The development of synthetic or semi-synthetic approaches may eventually reduce costs, though these approaches are still in research stages. Counterfeit and adulterated products remain a significant concern, with price points significantly below market averages often indicating potential quality issues.

For anxiety and sleep disorders, safranal offers moderate value compared to conventional anxiolytics and hypnotics. While effective, the high cost of pure safranal makes standardized saffron extracts (containing safranal along with other active compounds) a more cost-effective option for most consumers. For neuroprotection, the value proposition is low to moderate. The cost is significantly higher than many other neuroprotective supplements, though the multiple mechanisms of action may justify the premium for some users.

For anticonvulsant purposes, safranal represents poor value compared to conventional anticonvulsants, which provide more reliable and well-studied effects at lower costs. For antidepressant effects, the value is moderate, with effective doses requiring consistent use of relatively expensive supplements. For pain management, the value is low, with other natural analgesics providing similar benefits at lower costs. For cardiovascular protection, the value is low to moderate, with promising research but still requiring relatively high doses for significant effects.

Choose standardized saffron extracts (containing 0.3-0.5% safranal) rather than pure safranal supplements, as they provide better value while delivering effective doses, Look for supplements that combine saffron extract with synergistic compounds like L-theanine or GABA-enhancing herbs for better overall value, Subscribe to auto-ship options from reputable supplement companies, which often provide 10-15% discounts, Purchase larger quantities when possible, as the price per capsule is typically lower, For culinary use with some health benefits, Spanish saffron often provides better value than Iranian saffron, though the latter may have slightly higher safranal content, Avoid products with suspiciously low prices, as they are likely adulterated or of poor quality, Store properly to maintain potency and extend shelf life, reducing waste and replacement costs, Consider cyclodextrin-complexed safranal formulations, which offer better stability and potentially higher bioavailability, providing better value despite potentially higher initial cost

Pure safranal in liquid form, when properly stored, has a shelf life of approximately 1-1.5 years due to its volatile nature. Safranal in standardized saffron extracts typically remains stable for 1-2 years when stored properly, though the volatile safranal content gradually decreases over time. Encapsulated or tablet formulations of safranal generally have a shelf life of 1-2 years, depending on the excipients used and storage conditions. Liposomal or nanoparticle formulations of safranal may have enhanced stability, with shelf lives of up to 2 years under optimal storage conditions.

Cyclodextrin inclusion complexes of safranal show significantly improved stability, with shelf lives of up to 2-3 years. Safranal in saffron essential oil has a shelf life of approximately 1-2 years when stored properly in dark, airtight containers.

Store safranal and safranal-containing products in airtight, opaque containers away from direct sunlight, heat, and moisture. Ideal storage temperature is between 2-8°C (36-46°F) for pure safranal, though room temperature storage (15-25°C or 59-77°F) is acceptable for short-term storage of most formulations. Refrigeration is strongly recommended for liquid formulations containing safranal. Freezing is not recommended for most formulations as freeze-thaw cycles can accelerate degradation.

Vacuum-sealed packaging can significantly extend shelf life by reducing oxidation and preventing volatilization. Once opened, safranal products should be used within 3-6 months for optimal potency. Desiccants should be included in packaging for powder and tablet formulations to minimize moisture exposure. For essential oils containing safranal, storage in amber glass bottles with minimal headspace is recommended to reduce oxidation.

Volatilization is a primary concern for safranal due to its low boiling point (70°C at 1 mmHg), leading to loss of active compound even at room temperature, Oxidation of the aldehyde group and unsaturated bonds in safranal occurs readily upon exposure to air, converting it to less active compounds, Light exposure, particularly UV light, accelerates isomerization and degradation of safranal’s molecular structure, Heat significantly accelerates all degradation reactions, with marked degradation occurring above 30°C (86°F), Moisture can promote hydration of the aldehyde group and catalyze degradation reactions, pH extremes accelerate degradation, with safranal being most stable at slightly acidic to neutral pH (5-7), Metal ions, particularly iron and copper, can catalyze oxidation reactions, Microbial contamination can lead to both safety issues and enzymatic degradation of safranal

Synthesis Methods

Natural Sources

Quality Considerations

While safranal itself was not identified as a distinct compound until the 20th century, its source plant, saffron (Crocus sativus), has been used medicinally for thousands of years. The characteristic aroma of saffron, now known to be primarily due to safranal, was highly valued throughout history and played a significant role in its medicinal applications. Safranal was first isolated and characterized by Kuhn and Winterstein in 1933, who obtained it through the hydrolysis of picrocrocin and named this volatile compound ‘Safranal.’ Prior to its chemical identification, the aromatic properties of saffron were recognized as important indicators of its quality and potency. Ancient civilizations valued saffron not only for its color and flavor but also for its distinctive aroma, which we now know is primarily due to safranal.

In Ancient Persia (modern-day Iran), dating back to around 1500 BCE, saffron was used as a mood enhancer and sedative, applications that align with safranal’s now-known anxiolytic and hypnotic properties. The Persian physician Avicenna (980-1037 CE) described saffron’s use for insomnia and melancholy in his influential ‘Canon of Medicine,’ likely benefiting from safranal’s effects on the central nervous system. In Ancient Egypt, saffron was used in perfumes and aromatherapy, taking advantage of safranal’s pleasant aroma and potential psychoactive effects when inhaled. Egyptian medical papyri mention saffron’s use for various ailments, including as a sedative and pain reliever.

Ancient Greek physicians, including Hippocrates (460-370 BCE), prescribed saffron for sleep disorders and as a calming agent, applications that are consistent with safranal’s GABAergic effects. Dioscorides, in his 1st century CE work ‘De Materia Medica,’ noted saffron’s ability to induce sleep and relieve pain. In Traditional Chinese Medicine, saffron was classified as an herb that ‘vitalizes blood circulation’ and ‘relieves depression,’ effects that may be partially attributed to safranal’s cardiovascular and neuropsychological properties. In Ayurvedic medicine, saffron (known as ‘Kesar’) has been used for over 2,500 years as a treatment for insomnia, anxiety, and as a general tonic for the nervous system.

In medieval Islamic medicine, saffron was highly valued for treating melancholy, insomnia, and various neurological conditions. The 12th-century physician Ibn al-Baytar documented saffron’s use for ‘strengthening the brain’ and treating ‘diseases of the head.’ During the Middle Ages in Europe, saffron was used for treating melancholy (depression), promoting sleep, and calming anxiety, applications that align with safranal’s now-known effects on the central nervous system. In traditional Persian medicine, the aroma of saffron was considered particularly important for its therapeutic effects, suggesting an early recognition of safranal’s medicinal properties. The modern scientific understanding of safranal began in the early 20th century, with its isolation and characterization as a monoterpene aldehyde.

The specific pharmacological properties of safranal, distinct from whole saffron, have only been extensively studied in the past few decades, revealing its anxiolytic, anticonvulsant, antidepressant, and neuroprotective properties that align remarkably well with the traditional uses of its source plant. Today, safranal is recognized as one of the primary bioactive compounds in saffron responsible for many of its traditional medicinal applications, particularly those related to neuropsychological effects.

Evaluation of Safranal for Anxiety Disorders (Phase I clinical trial, estimated completion 2024), Safranal as an Adjunctive Treatment for Epilepsy (Phase II clinical trial, recruiting), Effects of Safranal on Sleep Quality in Insomnia Patients (Phase II clinical trial, estimated completion 2023), Safranal for Neuropathic Pain Management (Phase I/II clinical trial, planning stage), Cardioprotective Effects of Safranal in Patients with Ischemic Heart Disease (Phase I clinical trial, recruiting)