Therapeutic uses of saffron and its active ingredient safranal: An evidence-based review of human clinical studies

Saffron (Crocus sativus L.), also known as "red gold," is one of the world's most precious spices and has been used not only for culinary but also therapeutic purposes for over 4,000 years. The dried stigmas of the saffron crocus contain a variety of bioactive compounds, including the carotenoids crocin and crocetin, picrocrocin, and safranal. While crocin and crocetin are responsible for the characteristic color of saffron, picrocrocin determines its flavor, and safranal its distinctive aroma.

Scientific research into the medicinal properties of saffron has increased exponentially since 1980. Modern clinical studies confirm many of the traditional uses and show that saffron neuroprotective, mood-enhancing and anti-inflammatory properties owns.

Biochemical basics

The therapeutic effects of saffron are based on a multimodal action profile of its bioactive components. In vitro studies show an antagonistic effect on the serotonin type 2 receptor, inhibition of monoamine oxidase, and blockade of excitatory glutaminergic NMDA receptors. In addition, saffron stimulates the inhibitory GABA-A receptors.

Saffron exhibits potent antioxidant properties and protects against free radicals while promoting the production of the body's own antioxidant enzymes. Its anti-inflammatory properties are manifested by inhibiting the enzymatic activity of COX-1, COX-2, and iNOS, thereby reducing the production of prostaglandins. Furthermore, saffron inhibits the production of pro-inflammatory cytokines by inhibiting the NF-kappaB protein complex.

Safranal: Properties and effects

Safranal, a metabolite of picrocrocin, is primarily responsible for the characteristic aroma of saffron. Preclinical studies show that safranal has neuroprotective properties and can improve cognitive deficits in Alzheimer's modelsThe substance works by activating the AMPK signaling pathways and Induction of autophagy, thereby protecting neurons from amyloid-beta-induced toxicity. Safranal also inhibits acetylcholinesterase activity, which contributes to improving cholinergic function in neurodegenerative diseases.

Therapeutic applications

Depression and mood disorders

The antidepressant effect of saffron is well documented by numerous randomized controlled trials. A recent meta-analysis of eight randomized controlled trials with 656 adult participants showed that saffron is similarly effective as selective serotonin reuptake inhibitors (SSRIs) in reducing depressive symptoms. The dosage of a standardized saffron extract ranged from 15–60 mg per day for a period of 6–12 weeks.

A study of 128 adults with low mood showed a significant dose-dependent improvement in mood after four weeks of taking saffron extract. Participants reported a reduction in tension, depression, fatigue, confusion, anxiety, and stress, as well as increased energy.

Several direct comparison studies show that saffron has a comparable effectiveness to established antidepressants has.In controlled studies, saffron (30 mg/day) was found to be as effective as imipramine (100 mg/day) and fluoxetine (20 mg/day) in the treatment of mild to moderate depression. It is noteworthy that Saffron caused significantly fewer side effects than synthetic antidepressants.

Anxiety disorders

The anxiolytic properties of saffron have been demonstrated in both preclinical and clinical studies. A randomized, double-blind study of 56 healthy adults showed that eight weeks of supplementation with 30 mg of standardized saffron extract led to reduced depression scores and improved social relationships.

Particularly interesting is the observation that saffron attenuates the stress-induced decrease in heart rate variability (HRV) during psychosocial stressors. This suggests a specific effect on the parasympathetic nervous system and could explain the observed anxiolytic effects.

Studies with adolescents (12-16 years) with mild to moderate anxiety or depressive symptoms showed significant improvement in the symptoms examined after eight weeks of treatment. Another study with 54 participants over 12 weeks confirmed the antidepressant and anxiolytic effects in the treatment of depression and anxiety.

Alzheimer's dementia

The efficacy of saffron in Alzheimer's dementia has been studied in several high-quality clinical trials. A multicenter, double-blind controlled study with 55 patients with mild to moderate Alzheimer's dementia showed that Saffron (30 mg/day) was as effective as donepezil (10 mg/day) over 22 weeks, but without its side effects.

Another study with 46 patients demonstrated that saffron after 16 weeks of treatment significant improvement in cognitive performance compared to placebo. In a randomized study with 68 patients, Saffron extract (30 mg/day) over 12 months was more effective in reducing cognitive decline than memantine (20 mg/day) .

Diabetes mellitus

A comprehensive meta-analysis of ten randomized controlled trials involving 562 diabetic patients investigated the effect of saffron on glycemic parameters. Saffron supplementation (5 mg/day to 1 g/day) resulted in a significant reduction in fasting blood glucose (WMD = -8.42 mg/dL) and HbA1c (WMD = -0.22%) compared to placebo.

Clinical studies have shown multiple beneficial effects of saffron in diabetic patients, including improvements in metabolic factors, glycemic control, lipid profile, oxidative stress, and inflammatory parameters. Additionally, improvements in blood pressure, lung function, depression, anxiety, sleep quality, and life satisfaction have been observed.

Age-related macular degeneration

An open-label extension study of 93 adults over 50 years of age with mild to moderate age-related macular degeneration investigated the long-term effects of oral saffron (20 mg/day) over 12 months. Treatment resulted in a moderate but significant improvement in multifocal electroretinogram responses, including in patients already taking AREDS supplements.

Premenstrual syndrome

A double-blind, placebo-controlled study in women aged 20-45 years investigated the effects of saffron (30 mg/day) over two menstrual cycles. Saffron was found to be effective in relieving PMS symptoms, with significant differences in efficacy across treatment cycles in both the Daily Symptom Report and the Hamilton Depression Rating Scale.

Menopausal symptoms

A clinical study of 60 postmenopausal women with hot flashes and depression showed that saffron extract (30 mg/day) significantly improved both hot flashes and depressive symptoms over six weeks. Improvements were evident after just two weeks and persisted throughout the treatment period.

Cardiovascular effects

Preclinical and limited clinical data indicate that saffron may have beneficial effects on cardiovascular health. Animal studies have demonstrated cholesterol reductions of up to 50%, and saffron's antioxidant and anti-inflammatory properties may contribute to the maintenance of healthy arteries and blood vessels.

A clinical study conducted by the Department of Medicine and Indigenous Drug Research Center with 20 participants, 10 of whom had heart disease, demonstrated positive effects of saffron on cardiovascular parameters. Participants with cardiovascular disease showed greater improvements than the healthy control group.

Dosage recommendations

Dosages used in clinical studies vary depending on the indication. For the treatment of depression and anxiety disorders, 15-30 mg/day of a standardized saffron extract is typically used, divided into two daily doses. In Alzheimer's dementia, 30 mg/day has been shown to be effective.

Higher doses of up to 100 mg/day have been used in studies on metabolic syndrome, while for ophthalmic applications, 20 mg/day appears to be sufficient. One study showed dose-dependent effects, with 28 mg/day of saffron extract being more effective than 22 mg/day.

Safety profile and side effects

Saffron has a very favorable safety profile at the doses used in clinical studies (20-200 mg/day). A systematic review of twelve randomized controlled trials found no significant differences in adverse events between saffron and placebo.

Saffron should be avoided during pregnancy as it can stimulate labor.

Conclusion

Current studies show that saffron and its bioactive components, especially safranal, have a broad therapeutic spectrum. The strongest evidence exists for its use in depression and anxiety disorders, where saffron demonstrates comparable efficacy to established antidepressants with better tolerability. Clinical results are also promising in neurodegenerative diseases, particularly Alzheimer's dementia.

Other indications such as diabetes, macular degeneration, and gynecological conditions also show positive results, but require further confirmation through larger studies. The favorable safety profile and good tolerability make saffron an attractive option for patients seeking natural treatment alternatives.

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