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

Saffron (Crocus sativus L.), also known as "red gold," is one of the world's most precious spices and has been used for over 4,000 years, not only in cooking but also for medicinal purposes. 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, picrocrocin determines the flavor, and safranal the distinctive aroma of saffron.

Scientific research into the medicinal properties of saffron has increased exponentially since 1980. Modern clinical studies confirm many of the traditionally handed-down 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 at the serotonin type 2 receptor, inhibition of monoamine oxidase, and blockade of excitatory glutamatergic NMDA receptors. Additionally, saffron stimulates inhibitory GABA-A receptors.

Saffron possesses strong antioxidant properties and protects against free radicals while simultaneously promoting the production of the body's own antioxidant enzymes. Its anti-inflammatory properties manifest through the inhibition of 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-κB 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 possesses neuroprotective properties and can improve cognitive deficits in Alzheimer's modelsThe substance works by activating the AMPK signaling pathways and Induction of autophagySafranal protects neurons from amyloid-beta-induced toxicity. It also inhibits acetylcholinesterase activity, which contributes to improved cholinergic function in neurodegenerative diseases.

Therapeutic applications

Depression and mood disorders

The antidepressant effect of saffron is well documented in 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 to 60 mg per day over a period of 6 to 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 comparative studies show that saffron is a comparable efficacy to established antidepressants exhibits.In controlled studies, saffron (30 mg/day) proved 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 with 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.

Of particular interest 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 a relevant improvement in the symptoms studied 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 investigated 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, it proved to be Saffron extract (30 mg/day) over 12 months has been shown to be more effective than memantine in reducing cognitive decline. (20 mg/day) .

Diabetes mellitus

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

Clinical studies have shown multiple positive 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 with 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. The 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 effect of saffron (30 mg/day) over two menstrual cycles. Saffron proved effective in relieving PMS symptoms, with significant differences in efficacy between the treatment cycles as measured by both the Daily Symptom Report and the Hamilton Depression Rating Scale.

Menopausal symptoms

A clinical study with 60 postmenopausal women experiencing hot flashes and depression showed that saffron extract (30 mg/day) administered over six weeks resulted in a significant improvement in both hot flashes and depressive symptoms. Improvements were noticeable after just two weeks and persisted throughout the entire treatment period.

Cardiovascular effects

Preclinical and limited clinical data suggest that saffron may have positive 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 maintaining healthy arteries and blood vessels.

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

Dosage recommendations

The dosages used in clinical trials vary depending on the area of ​​application. 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 proven effective..

Higher doses of up to 100 mg/day have been used in studies on metabolic syndrome., while 20 mg/day appears to be sufficient for ophthalmic applications. 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, at the dosages used in clinical trials (20-200 mg/day), exhibits a very favorable safety profile. 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 research shows 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 areas of application, 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.

Sources:

· Freiburg University Hospital, saffron – the plant gold has many uses, university hospital-freiburg.de/fileadmin/medi…

· Burgerstein Foundation, Saffron for Depression » clinical studies on its effectiveness, burgerstein-foundation.ch/de-DE/fachbere…

· Orthoknowledge Foundation, Summary Saffron The Red Gold orthoknowledge.eu/summary…

· NHS Health Research Authority, SAFFRON, hra.nhs.uk/planning-and-i…

· Neurolab.euSaffron as an alternative for depression...

· Georg Thieme Verlag KG, Medicinal Plants: Saffron – the plant gold has many uses, natuerlich.thieme.de/therapy procedure…

· Papandreou et al. (Current Neuropharmacology), Crocus Sativus L. (Saffron) in Alzheimer's Disease Treatment, 2022, pmc.ncbi.nlm.nih.gov/articles/PMC8765911/

· Safarinejad et al. (Nature), An open label, randomized, fixed-dose, crossover study comparing ... (Erectile Dysfunction), 2010, nature.com/articles/ijir201013

· Piccardi et al. (BMJ Open Ophthalmology), Saffron therapy for the ongoing treatment of age-related macular ..., 2022, pmc.ncbi.nlm.nih.gov/articles/PMC10086835/

· Akhondzadeh et al. (PubMed), Crocus sativus L. (saffron) in the treatment of premenstrual syndrome, 2008, pubmed.ncbi.nlm.nih.gov/18271889

· Milajerdi et al. (Nutrition and Metabolic Insights), A review of the anti-diabetic potential of saffron, 2022, pmc.ncbi.nlm.nih.gov/articles/PMC9345447/

· Milajerdi et al. (Sage Journals) A review of the anti-diabetic potential of saffron, 2022, journals.sagepub.com/doi/abs/10.1177/11786388221107165

· Mazidi et al. (Frontiers in Nutrition), Effect of saffron supplementation on the glycemic outcomes in ..., 2021, frontiersin.org/journals/nutrition/articles/10.3389/fnut.2021.696087/full

· Lopresti et al. (Frontiers in Nutrition), Effects of Saffron Extract Supplementation on Mood, Well-Being, and ..., 2021, pmc.ncbi.nlm.nih.gov/articles/PMC7847292/

· Moshiri et al. (Iranian Journal of Basic Medical Sciences), Saffron and its active ingredients against human disorders, 2022, pmc.ncbi.nlm.nih.gov/articles/PMC9442340/

· Razavi et al. (Evidence-based Complementary and Alternative Medicine), Bioaccessibility and Pharmacokinetics of a Commercial Saffron ..., 2019, pmc.ncbi.nlm.nih.gov/articles/PMC7043156/

· Modaghegh et al. (The Journal of Tehran Heart Center), Cardiovascular Effects of Saffron: An Evidence-Based Review, 2010, pmc.ncbi.nlm.nih.gov/articles/PMC3349809/