1. Introduction: Dried stigmas of the perennial flower Crocus sativus Linn (Iridaceae) produce a valued herb: Saffron. Dubbed as "red gold" and "golden condiment," Saffron has been named in cookbooks and pharmacopeias throughout history and geography, including Ebers papyrus (Egyptian, 1550 BC), Apicius (Roman, 1st century), Materia Medica (Greek, 1st century), Avicenna's Canon of Medicine (Persian, 11th century), and Indian Ayurvedic literature [1–5]. Furthermore, it also serves as a dye in food products and textiles and as an aromatic in perfumes and cosmetics. These dried floral constituents are most often the vibrant stigmas of the flower but sometimes also include styles and other floral tissue (e.g., filaments) [6]. The herb is red and has a bitter taste and a pleasant fragrance. It has been employed in traditional medicine as an antidepressant, anti-carcinogen, stimulant, and many other functions [1,7].

Of this asexual reproduction, no breeding efforts can be employed, limiting improvements to the selection of advantageously mutated corms. Only slight morphological and biochemical differences exist between these clones geographically. Morphological abnormalities rarely occur. This usually manifests in more or less than three-branched stigmas through the fusion of flowering buds [8]. Saffron's value is tied to its limited production methods. Harvesting is a laborious manual process and challenging to mechanize [9,10]—saffron flowers in the autumn. Harvesting is only possible upon first bloom, as the frost of the superseding night will damage the flower. Therefore, harvesting is only done on a per-flower basis. The subsequent separation of the styles and stigmas is also often manual work, where the worker must ensure the herb is not damaged.

Ancient civilizations recognized Saffron's therapeutic effects in the second millennium B.C. Assyrians and Babylonians employed Saffron as a medicine against dyspnea, neurological disorders, menstruation, and painful urination [11]. The Greeks used Saffron against insomnia, addiction withdrawal, and hangovers [1]. The Egyptians used it as an incense with sedative qualities [12]. Saffron's therapeutic effects are copious, as seen in Table 1.

Table 1. Reported functions of Saffron and its extracts in experimental trials.

Function Experimental Findings Reference Diuretic agent Doses of 120 and 240 mg/kg B.W. have shown diuretic activity in rats; however, they are at lower activity than hydrochlorothiazide. [13] Analgesic agent Safranal, ethanolic, and aqueous Saffron extracts acted as analgesic agents in animal models. [14] Aqueous Saffron extracts reduced pain in rats dose-dependently during the chronic phase of the formalin test. [15] Anti-nociceptive Aqueous and ethanolic extracts of stigmas and petals reduced pain signaling from acetic acid-induced writhing. [16] Anti-inflammatory Ethanolic Saffron stigma extracts exhibited edema inhibition, with a coagulation time similar to aspirin's. [17] Stigma extracts showed weak to moderate effects against acute xylene inflammation in mice. However, both stigmas and petal extracts exerted anti-inflammatory effects in edema-induced chronic inflammation in rats. [16] Anti-convulsant Aqueous and ethanolic extracts of stigmas retarded the initiation and duration of tonic convulsions in mice. [18] Bronchodilatory Concentrations varying between 4 and 16 mg/mL of safranal had a preventive effect on the tracheal responses in guinea pigs. [19] Secretagogues/anti-diabetes A combination of resistance exercise and 40 mg/kg/day of Saffron administration improved diabetes parameters, including insulin release and glucose uptake, in rats. [20] Hepatoprotective 20 mg/kg doses of Saffron petal hydroalcoholic extracts reduced acetaminophen-induced liver toxicity in rats. [21] 100 mg/kg doses of Saffron hydro- and alcoholic extracts prevented liver injury in rabbits with prolonged exposure to amiodarone. [22] 80 mg/kg ethanolic extracts of Saffron significantly reduced hepatic injury biomarkers during exposure to rifampin. [23] Anti-carcinogenic Aqueous Saffron extracts achieved a chemopreventive effect in mice. However, this was not consistently dose-dependent. [24]

The present study overviews Saffron, its constituent Crocin as an antidepressant in historical medicine, and the modern evidence. To this end, Scopus and Google Scholar were queried for reports on the pharmacological activities of Saffron constituents, with a particular focus on Crocin, relating to mechanisms of depressive disorders. Additionally, the bioavailability of Crocin and delivery mechanisms were investigated.

2. Depression and Associated Disorders and the Role of Natural Products as Adjunct Therapy

Depressive disorders are a group of emotional states centering around sadness—these range in severity, varying from unhappiness and discontent to debilitating hopelessness [28]. Two predominant depression disorders are persistent depressive disorder (PDD) and major depressive disorder (MDD). PDD, or dysthymia, typically endures longer but with less severity than MDD. A variation on MDD, bipolar disorder (or, formerly, manic depression), is accompanied by episodic mania [29]. Other types of depression are recognized, e.g., perinatal depression, seasonal affective disorder, and psychotic depression. Depression severities are commonly classed with the aid of the Hamilton Depression Rating Scale (HAM-D) [30].

The mechanisms of depression are still theorized but generally point to a deficiency. Recessions are explained through the monoamine theory by a lack of three neurotransmitter molecules: serotonin, norephedrine, and dopamine. Alternatively, the more recent neurogenic theory ascribes a deficiency of neurons to cause depression. Medication, psychotherapy, brain stimulation therapy, or a combination thereof can be employed as curatives [31]. Pharmacological treatments aim to either inhibit neurotransmitter reabsorption (e.g., selective serotonin reuptake inhibitors (SSRIs), selective serotonin and noradrenaline reuptake inhibitors (SSNRIs), or tricyclic antidepressants (TCAs)) or inhibit neurotransmitter-degrading enzymes (monoamine oxidase (MAO)), distinguishable in MAO isoform A (affinitive to serotonin and somewhat norepinephrine) and B (acting strongly on phenylethylamine and benzylamine) [32,33].

Depressive disorders have consistently had a significant impact on global DALYs. This burden has recently increased, exacerbated by the COVID-19 pandemic [34]. Natural officinal remedies have been reported throughout history. For instance, traditional Chinese medicine has employed Panax ginseng root for millennia as a mood enhancer [35,36]. Xu et al. [37] found that ginsenosides, particularly (S)-protopanaxadiol, exhibited strong antidepressant effects in rats.

Similarly, peony extract, a Paeonia lactiflora root derivative, was used as an antidepressant in traditional Chinese medicine. Indeed, peony has been shown to exhibit anti-depressant-like effects in stressed rodents [38]. Moreover, the Ginkgo biloba seeds have been employed in traditional Chinese medicine for their neuro-protective results [39]. Curcuma has been incorporated into both traditional Indian and Chinese medicine to regulate stress and mood disorders [40,41]. Chlorophytum comosum has traditionally been used in traditional medicinal preparations in India, China, and Africa, with the constituent stigmasterol exerting neuroprotective effects [42].

Tea spread from China to Japan as medicine, later described in the Japanese book Kissa Youjouki as a marvelous medicine preventive for many ailments [43]. Catechins in green tea have experimentally been shown to act as a possible MAO inhibitor in mice [44,45]. Similarly, many other plant molecules/extracts are psychotropic in experimental models (Table 2).

3. Saffron: Reported Biologically Active Compounds and Their Pharmacology

Saffron herb is host to a plethora of bioactive compounds, including carotenoids (crocetin, Crocins, α-carotene, lycopene, and zeaxanthin), monoterpene aldehydes (e.g., picroCrocin and safranal), monoterpenoids (e.g., crocusatines), isophorones, and flavonoids [2,55]. Crocetin and its glycosidic analogs Crocin, picrocrocin, and safranal are the most notable bioactive molecules [56]. A myriad of pharmaco-active functions is attributed to these compounds.

Saffron's aroma is chiefly attributed to the volatile compound safranal (Figure 1A). Safranal attenuated oxidative damage induced through cerebral ischemia in rats [57]. Research has found that safranal acts on neurological disorders. For instance, safranal proved an effective anti-convulsant in mice, whereas Crocin did not [58]. Similarly, Hosseinzadeh and Sadeghnia [59] found safranal protection against seizures in rats. Other studies on mice have attributed antidepressant properties to safranal and Crocin via inhibiting dopamine, serotonin, and norepinephrine reuptake [60,61].

Crocetin (Figure 1B) and Crocins were shown to inhibit in vivo and in vitro angiogenesis, with crocetin being more efficacious [66]. Thus, crocetin could be employed to retard abnormal blood vessel growth. Furthermore, crocetin is anti-carcinogenic. Its mechanisms include inhibiting nucleic acid synthesis, enhancement of anti-oxidative systems, apoptosis initiation, and growth hindrance of signaling pathway factors [67]. Conflictingly, Escribano et al. [68] attributed no cytotoxic effect to crocetin, whereas the other three compounds did inhibit cell growth.

Crocins, the molecules of the subject in this paper, are carotenoids jointly responsible for Saffron's vibrant color. Several of Saffron's curative functions can be related to this group of compounds. It has acute and chronic anti-inflammatory effects. This has been demonstrated in both in vitro cyclooxygenase inhibition assays and in vivo tests with edemas in rodents [69]. Moreover, it has in vivo been shown to relieve cerulein-induced pancreatic inflammation [70].

Furthermore, Crocins can alleviate neurological disorders. Georgiadou et al. [71] alleviated

manually induced schizophrenia-like behavior in rats by administering Crocins. Lastly, Crocins exhibited antidepressant activity through neurotransmitter reuptake inhibition. This has been demonstrated in vivo and in vitro [61,72,73]. Notably, crocetins are more readily absorbed than Crocins in the gastrointestinal tract of animals [74]. Crocins are metabolized to crocetins when administered orally [74–76]. However, how readily Crocin is metabolized in humans has not yet been elucidated. Nevertheless, the method of administration must be significant for pharmacokinetics.

Figure 1. Structural formulas of Saffron constituents safranal (A) [61], trans-crocetin (B) [62], picroCrocin (C) [63], and trans-crocetin digentiobiose ester (D) [64], one of Crocin’s many forms [65].

PicroCrocin (Figure 1C), a colorless, bitter-tasting compound, shares therapeutic effects with the other three compounds (e.g., anti-carcinogenic) [68]. However, studies on isolated picroCrocin are limited to our knowledge, and its role as a neuroprotective agent has yet to be described [77].

 

Read About Pain Management by Saffron

 

4. Role of Saffron Stigma Extract and Crocin in Synaptic Transmission

Crocins are natural carotenoids, commercially obtained from the dried stigma of Saffron, occurring with different esterified saccharides on a crocetin backbone, such as transcrocetin (β-D-glucosyl)-(β-D-gentiobiosyl) ester (named trans-3-Gg), trans-crocetin di-(β-Dglucosyl) ester (named trans-2-gg), trans-crocetin di-(β-D-gentiobiosyl) ester (named trans-4GG; Figure 1D), trans-crocetin (β-D-gentiobiosyl) ester (called trans-2-G), cis-crocetin (β-Dglucosyl)-(β-D-gentiobiosyl) ester (named cis-3-Gg), and cis-crocetin di-(β-D-gentiobiosyl) ester (named cis-4-GG). Saffron's brick-red color is generally a result of the glycoside carotenoid structure of Crocin [78]. Moreover, the main interest in this herb could be due to its anti-anxiety, anti-convulsant, and hypnotic properties. Bioactive compounds such as Crocin, crocetin, and others are believed to be attributed to their anti-oxidant properties, which may partly justify their neuroprotective effects [79].

Several studies have demonstrated that Saffron not only inhibits the reuptake of monoamines but also exhibits both N-methyl-D-aspartate (NMDA) receptor antagonism and γ-aminobutyric acid agonism, which seem to be responsible for its anti-depressant-like and anxiolytic effects demonstrated in animal models [80]. It was concluded from the human and animal studies that Saffron, mainly Crocin, has shown a positive impact on the treatment of mild to moderate depression, which might be possibly due to the interaction of serotonin and the noradrenaline system [81].

According to the studies of various parts of the Saffron flower, contractile responses to electrical field stimulation (EFS) in isolated vas deferens in rats were reduced by Saffron petal extracts. The contractions of EFS-induced vas deferens were shown to be mediated by noradrenaline and adenosine triphosphate from sympathetic nerves. The ethanolic extract of Saffron was noted to show changes in EFS in rats' isolated vas deferens; however, the aqueous extract of Saffron was more effective in guinea pig ileum [82]. Saffron and Crocin were found to have an inhibitory impact on amyloid beta-peptide fibrillogenesis and a protective action against H2O2-induced toxicity in human neuroblastoma cells in an in vitro study. After a week of administration, Saffron (60 mg/kg body weight, i.p.) significantly increased learning and memory in normal and old mice, demonstrating cognitive-enhancing properties [83]. In another study, Crocin activity was linked with reactive oxygen species production and causing oxidative stress; for instance, by the treatment with 5 and 25 mg/mL of Saffron extract, 10 and 50 µM of Crocin lowered the neurotoxic effect of glucose in ROS-mediated PC12 cells [84].

Some clinical studies have shown that Saffron supplementation statistically improved subjects' mood in a randomized and double-masked study compared to the placebo group. For six weeks, the administration of Saffron extract (30 mg/day) was influential in the treatment of mild to moderate depression based on the HAM-D. These effects were similar to the effects of fluoxetine, which is an antidepressant known as an SSRI [85,86]. The therapeutic benefits of saffron petals in treating mild to moderate depression have also been suggested [87]. The efficacy of the co-administration of a hydroalcoholic extract of Saffron (40 or 80 mg) and fluoxetine (30 mg/day) was also investigated in a double-masked, randomized clinical trial for six weeks. The results revealed that a dose of Saffron of 80 mg plus fluoxetine was more effective in treating mild to moderate depressive disorders than that of Saffron of 40 mg and fluoxetine [88].

5. Monoamine-Related Mechanism and Brain Neurotransmitters

All antidepressant drugs increase the monoamine concentration in the brain; therefore, it is essential to note that depression is defined by the severe condition of brain monoamine reduction [89]. The MAO inhibitory properties of Crocin and safranal were evaluated to assess their influence on catecholamine and 5-HT levels in the brain. In particular, Crocin was demonstrated to be a non-competitive inhibitor of the human MAO-A and MAO-B in the micromolar range using binding to allosteric sites on the enzyme, whereas safranal was inactive toward both isoforms. It is known that MAO-A and MAO-B are two essential enzymes that are targets for treating neurodegenerative disorders [90]. Saffron extract co-administered with aluminum-induced changes in MAO (A and B) activity and the levels of lipid peroxidation in the whole brain and cerebellum [81].

The emergence of depression is associated with several physiological disturbances in monoaminergic activity, hypothalamus-pituitary-adrenal activity, inflammation, and oxidative and nitrosative stress [91]. Crocin is a group of hydrophilic carotenoids consisting of an esterified monoglycosyl or disaccharide gentiobiose on the dicarboxylic acid crocetin [92]. The possible molecular mechanisms suggest that Crocin exerted anti-inflammatory activity in a rabbit osteoarthritic model by inhibiting interleukin-1 beta-induced activation of the nuclear factor-kappa B NF-kB pathway [93]. Furthermore, Crocin decreased the mRNA expression of tumor necrosis factor α (TNF-α), IL-1β, IL-6, interferon-γ (IFN-γ), NF-κB, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) [94].

In another mechanism hypothesis, brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily, which includes growth factors that promote learning and memory by cell survival, differentiation, and death of specific neuronal populations. The epigenetic modulation of BDNF and TRKb genes might contribute to the pathophysiology of depression and related behaviors [93,95]. The anti-depressant-like activity increases the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), BDNF, and VGF levels in the hippocampus [96]. Another vital family involved in the mechanism belonging to serine/threonine protein kinases is mitogen-activated protein kinases (MAPK), which regulate neuronal activity and synaptic plasticity. Activation of the MAPK cascade requires four sequential events, which include small GTPases (Ras and Rac proto-oncogenes), MAPK kinase kinases (Raf or MEKK), MAPK kinases (MEK), and MAPKs—the activation of the MAPK cascade links the extracellular signals to synaptic responses [96]. The Ras-Raf-MEK1/2 pathway is responsible for activating extracellular signal-regulated kinase (ERK), which plays a pivotal role in psychiatric disorders, including depression and anxiety [97]. High concentrations of Crocin significantly reduced p-MEK. Therefore, modulation in the BDNF/CREB/ERK signaling cascade and inhibition through Crocin might provide further insights into the importance of behavioral changes during depression [96].

The expression of pituitary adenylate cyclase-activating polypeptide (PACAP) is inhibited by stress, which results in the inhibition of the phosphorylation of extracellular regulated protein kinases (ERK) and response element binding protein (CREB) and results in the reduction of the translation of synaptic plasticity proteins, which untimely causes depression, as shown in Figure 2A [98]. Saffron Crocin can upregulate endogenous PACAP, resulting in the activation of ERK and CREB. This will improve synaptic plasticity and enhance neuronal survival, as shown in Figure 2B. This mechanism has been reported based on mice and corticosterone cell models.

Figure 2. Mechanism for the neuroprotective effect of Crocin in depression. Stress can cause depression (A); however, Saffron Crocin can reduce the impact of stress by exhibiting neuroprotection activity (B). PACAP, pituitary adenylate cyclase-activating polypeptide; ERK, extracellular regulated protein kinases; CREB, response element binding protein; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; A.C., adenylyl cyclase [98].

The Saffron extract is involved in inhibiting serotonin reuptake in synapses, enhancing its positive effects while combating depression. Research suggests that the reuptake inhibition of monoamines, MAO inhibition, NMDA antagonism, and improved brain-derived neurotrophic factor signaling may be mechanical factors responsible for treating depression from Saffron [99].

6. Neurotransmitter Receptors and Possible Targets for Crocin

The cholinergic synapses in the human central nervous system are responsible for transmitting critically essential brain functions such as memory, learning, attention, etc. [81]. Antidepressants are reported to function by triggering serotonin, norepinephrine, and dopamine levels in the brain. To confirm this, Ettehadi et al. [100] measured changes in rat brain dopamine, serotonin, norepinephrine, and glutamate concentrations after the administration of an aqueous extract of Saffron (50, 100, 150, and 250 mg/kg, i.p.), Saffron increased brain dopamine concentration in a dose-dependent manner. In addition, the results showed that the aqueous extract of Saffron, especially at the dose of 250 mg/kg, increased the production of essential neurotransmitters, including dopamine and glutamate, in rat brains [100]. It was reported based on animal studies that the possible antidepressant activity of Saffron bioactive compounds (Crocin and safranal) could be mainly through inhibiting serotonin reuptake and the inhibition of dopamine and norepinephrine reuptake (Figure 3) [101].

Figure 3. Illustration of the mechanism of inhibition of norepinephrine (N.E.) reuptake and serotonin reuptake by (A) Crocin and (B) Safranal, respectively [101].

The effects of Saffron on conditioning place preference induced by morphine have been reported to be similar to the effect of NMDA receptor antagonists [102]. Therefore, an interaction of Saffron and glutamate receptors in the nervous system might be postulated in the glutamatergic system. The high calcium permeability through NMDA receptors plays an essential role in post-training memory processing by the amygdala and hippocampus parts of the brain [103]. Similarly, the cholinergic system imparting learning and other higher brain functions in the central nervous system have also been mediated by the effect of Saffron extract [104,105]. Therefore, there are requirements for more mechanistic-based experiments to study the involvement of Saffron extract in cognition and depression.

6.1. Serotonin

It was observed from the abovementioned studies considering a biochemical point of view that Crocin from Saffron is proven to be able to find a balance with a highly complex mechanism with some of the major neurotransmitters, such as in serotonergic activity, in which each type of neurotransmitter carries specific information and creates a unique set of an individual's brain chemistry. In addition to that, saffron has been reported to modulate the hypothalamus-pituitary-adrenal (HPA) axis and impart a neuroprotective effect. Saffron is said to increase superoxide dismutase, catalase, and glutathione peroxidase levels while lowering malondialdehyde levels and inhibiting the lipid peroxidation pathway. Moreover, Saffron positively influences brain plasticity in which the ability of neural networks increases through growth and reorganization [106].

6.2. Dopamine

To identify cellular and molecular mechanisms underlying the antidepressant property of Saffron, it is essential to measure another important neurotransmitter commonly responsible for creating positive feelings associated with reward or reinforcement activity. In recent studies, Saffron was accountable for treating mild to clinical depression. The findings suggested that an aqueous extract of Saffron contains an active component that possibly accelerates dopamine and glutamate levels in the brain suffering from depression [100]. Due to the complex anatomy of the brain, it is difficult to investigate whether dopamine and glutamate are released in the vesicles or the synaptic space; however, both the aqueous and organic extracts of Saffron showed significant results in reducing symptoms of depression.

7. Pharmacological Treatment of Depression with Crocin

Several pharmacological activities have been suggested to be involved in the antidepressant-like effects (Table 3). In the following section, we discuss these potential treatments and the impact of Saffron on mild, moderate, and major depression. The emerging interest in herbal medicine for depression will eventually replace the long-standing reliance on synthetic antidepressants; for example, Saffron has gained a reputation to be used as a natural source to fight the symptoms of depression. The studies showed the effect of Saffron's stigma was as effective as chemically derived antidepressants such as imipramine and fluoxetine in mild to moderate depression [85,86]. Similarly, Saffron was equally effective as citalopram in major depressive disorder with anxious distress [107] and decreased mild to moderate generalized anxiety disorder when compared with sertraline [108].

Table 3. Studies on pharmacological activities relating to anti-depressant-like effects of Saffron. BDI, Beck depression inventory; HAE, hydroalcoholic extract; PCI, percutaneous coronary intervention; CAD, coronary artery disease; HAM-D, Hamilton Depression Rating Scale; PMS: premenstrual syndrome; GAD, generalized anxiety disorder; MMT, methadone maintenance treatment.

Aim of the Research Type of Study No. of Patients Treatment Time of Treatment (Weeks) Results References Saffron versus citalopram in the major depressive disorder with anxious distress Double-blind, controlled, clinical trial 66 30 mg, Saffron stigma 6 Effective against moderate to major depression. [107] Saffron as an add-on therapy to sertraline in mild to moderate generalized anxiety disorder Double-blind, randomized, controlled trial 40 A 500-mg capsule containing 450 mg of Saffron (type not recorded) 6 Decreased mild to moderate generalized anxiety disorder with Saffron, as well as with sertraline. [108] Comparison of petal of Saffron and fluoxetine Double-blind, randomized trial 40 Petal of Saffron, 15 mg/day (morning and evening) 8 Petal of Saffron was found to be similarly effective to fluoxetine in the treatment of mild to moderate depression. [87,110] 40 and 80 mg HAE of Saffron against fluoxetine Double-blind, randomized, clinical trial 60 Saffron, 40 and 80 mg/day + fluoxetine (30 mg) 6 Effective in the treatment of mild to moderate depressive disorders. [88,111] Saffron with fluoxetine in PCI patients Double-blind, randomized, clinical trial 40 Saffron (30mg/day) 6 Effective as fluoxetine (40 mg/day) in improving depressive symptoms of patients who were suffering from major depressive disorder (MDD). [112] Saffron and Crocin in improving mental and sexual health in CAD patients Double-blind, placebo- controlled, randomized, clinical trial 58 Stigma of Saffron, 30 mg/day OR 8 The outcome of BDI-II scores significantly decreased after eight weeks of intervention. [113] Saffron in the treatment of PMS Double-blind, randomized, and placebo- controlled trial 50 30 mg, Saffron petal during premenstrual syndrome 8 The depression measured significantly decreased. [114] Crocin on depression in subjects with metabolic syndrome Randomized, double-masked, controlled clinical trial 33 30 mg, Saffron (Crocin) 8 Decreased depressive symptoms in patients with metabolic syndrome. [115] Saffron improved depression and reduced homocysteine level in patients with major depression Randomized, double-masked study 40 30 mg, Saffron (stigma) and 20 mg, fluoxetine 4 The BDI score decreased in patients with major depression. [116] Comparison of Saffron versus fluoxetine in treatment of mild to moderate post-partum depression Double-blind, randomized, clinical trial 60 30 mg, Saffron (stigma) 6 Significantly decreased mild to moderate depression and post-menopausal hot flashes. [110] Crocin in major depressive disorder Randomized, double-masked, placebo- controlled, pilot clinical trial 78 30 mg, Saffron (stigma) 8 Significant decrease in mild to moderate depression. [111] Affron®, a standardized extract from Saffron Randomized, double-masked, placebo- controlled study 80 14 mg, Saffron (stigma) 8 Significant reduction in mild to moderate depression. [117] Saffron in the treatment of anxiety and depression Double-blind, randomized, and placebo-controlled trial 60 100 mg, Saffron (stigma) 12 Significant decrease in mild to moderate depression. [118] Saffron (petal) in the treatment of mild to moderate depression Double-blind, randomized, and placebo- controlled trial 36 30 mg, Saffron (stigma) and 40 mg, fluoxetine 4 There was no significant decrease. [119] Effects of Saffron on depression and lipid profile Double-masked comparative study 40 30 mg, Saffron (petal) 6 Decrease in significant depression of those who met DSM-IV criteria. [109] Saffron stigma in mothers suffering from mild to moderate post-partum depression Double-blind, randomized, placebo- controlled trial 40 30 mg, Saffron (type not recorded) and 20 mg, fluoxetine 4 Significant decrease in major depression. [120] Crocin on Psychological Parameters in patients under MMT Randomized clinical trial 46 30 mg, Saffron (Crocin) and 20 mg fluoxetine 4 Significant decrease in major depression. [121] Crocin on Psychological Parameters in patients under MMT Randomized, double-masked, placebo- controlled trial 50 30 mg per day, Saffron (Crocin) 8 Improved depression symptoms during methadone maintenance treatment (MMT). [122]   Double-blind, randomized, and placebo-controlled trial 28 150 mg per day, Saffron 6 Increased serotonin and happiness were further heightened in supplemented group. Anandamide, dopamine, and β-endorphin were significantly increased under supplementation, whereas the placebo remained unchanged. [123]

Other parts of Saffron, such as petals, proved effective on the HAM-D in treating depression [109]. In addition, comparing the results in depressed adult outpatients, it was concluded that the petals of Saffron were as effective as the synthetic antidepressant fluoxetine [87]. Even in a randomized clinical trial, fluoxetine was given with a regulated amount of Saffron (40 and 80 mg/day) and showed promising results in the treatment of mild to moderate depression [88]. Saffron significantly decreased the mild to moderate depression in those with post-menopausal hot flashes when compared to fluoxetine [110].

Saffron stigma was shown to reduce mild to moderate post-partum depression in mothers [111]. It was also found to be effective during mild to moderate depression in patients suffering from post-percutaneous coronary intervention [112]. Likewise, an aqueous extract of Saffron and its Crocin was found to significantly improve mild to moderate depression in patients with coronary artery disease [113]. Additionally, there was a significant decrease in the treatment of depression during premenstrual syndrome [114]. Crocin showed lower symptoms of depression in subjects with metabolic syndrome [115]. Saffron comparably improved depression and dysfunction, such as reduced homocysteine levels in patients with major depression [116]. Affron®, a standardized extract from Saffron, showed a significant reduction in mild to moderate youth anxiety and depressive symptoms [117].

As mentioned in the above studies, the stigma of Saffron showed a significant decrease in mild to moderate depression [118], and the petals of Saffron were used to improve signs of major depression [109]. Compared to fluoxetine, Saffron reduced depression and improved the lipid profile [120]. Crocin also showed a significant decrease in major depression [121]. Similarly, Crocin had effects on psychological parameters in patients under methadone maintenance treatment to improve depression-like symptoms [122]. Results revealed that there is enormous potential for accepting Saffron as an herbal drug for the treatment of mild to moderate depression; however, more research is required for it to be taken against significant depression. Table 3 depicts an overview of studies employing Saffron and Crocin as antidepressants.

Crocins have been demonstrated to be potentially applicable as an antidepressant. However, Crocins are poorly bioavailable, with a small percentage permeating the digestive tract [124]. Furthermore, Crocins are deglycosylated into crocetin through hydrolysis when orally ingested [56,124,125]. Intraperitoneal injection does allow unaltered Crocins to penetrate the blood–brain barrier [126]. Nevertheless, drug stability and bioavailability should be increased so as not to hamper the desirable ad oral ingestion. Nanocarriers have been demonstrated to be applicable aids in biological delivery processes [119,123,127]. Various matrices have been shown to increase and retain Crocins, increasing delivery and stability (Table 4). The exploitation of nanomaterials poses a promising route. However, the efficacy of gastrointestinal tract and blood–brain barrier permeation and Crocin hydrolysis remains unspecified in most cases.

 

Table 4. Effect of experimental drug delivery systems on Crocin's stability, loading, and bioavailability, as reported in the literature.

Matrix Results Reference Chitosan-alginate nanoparticles The highest Crocin loading was achieved at pH 1.2 with a biphasic release in simulated gastric fluids. The loaded nanoparticles were equivalent in DPPH free radical scavenging and ferric-reducing ability of plasma as free Crocin and exhibited an anti-cancer effect. [128] Maltodextrin nano encapsulates Nanoencapsulated Crocin was more stable at simulated gastrointestinal conditions. While encapsulation increased bioaccessibility (from 61% to 72%), combining caffeic acid with encapsulation increased the bioaccessibility to almost 80%. [129] Maltodextrin/pectin/whey protein concentrate nano encapsulates Combinations of whey protein concentrate and pectin yielded the highest Crocin encapsulation efficiencies, exceeding 95%. Thus, minimal amounts of Crocins were exposed to the particles' surfaces. Furthermore, improved stability against stressors was suggested. [130] Chitosan-gum arabic nanoencapsulates Crocin was encapsulated with an efficiency of 29 to 52%. The release profiles showed an oscillatory relationship with time at pH 1 and 2. This oscillatory relation was suggested to result from the rapid degradation of released Crocin. [131] Cholesterol-Tween 40 nanoniosomes Encapsulation efficiency was 46%, and 61% of Crocin was released after six hours in mice. Intra-arterially injected Crocin-laden niosomes decreased ischemic indicator molecules in rats and mitigated I/R tissue damages. [132] Bacterial nitrocellulose membrane The nitrocellulose membrane exhibited a stable and prolonged transdermal release through mice's skin in a Franz diffusion cell. [133] Chitosan-alginate An encapsulation efficiency of 92% was attained. The resulting nanoparticles stabilized Crocin degradation at pH 2, enhanced bioavailability, and showed a pH-mediated release. [134] Solid lipid nanoparticles Increased stability and high encapsulation efficiency. [135] Selenium nanoparticles The crocin release rate was pH dependent, with 91% released after 48 h at pH 5.3, whereas just a mere 35% was released at pH 7.4 during the same time. The administration of loaded nanoparticles enhanced cytotoxicity in lung cancer cells and inhibited tumor growth in a mouse model. [136] Poly(lactic-co-glycolic acid) nanoparticles Entrapment efficiency reached 59%, and 78% of Crocin was released after 24 h at pH 7.4, sustaining release throughout 48 h. Release was increased from pH 6.5 to 84% after 24 hours. [137]

 

8. Conclusions and Future Perspectives

For ages, people have preferred the dried stigma of Crocus sativus (Saffron) for medicinal and nutritional purposes in different parts of the world, mainly in Central Asia, Iran, China, India, Turkey, Algeria, and Europe. The most active biological compounds include crocetin, Crocin, picrocrocin, and safranal, responsible for color, taste, and fragrance. These play a pivotal role in the central nervous system associated with anxiety and depression. These bioactive compounds are also neuroprotective and anxiolytic and can benefit learning and memory impairments. The most popular antidepressants that physicians prescribe are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin noradrenaline reuptake inhibitors (SSNRIs).

The primary mechanism works by enhancing serotonin, a particular neurotransmitter.

The high cost of Saffron is due to labor-intensive production, which initially requires handpicked stigmas for Saffron. These precious stigmas contain all the bioactive compounds responsible for their medicinal properties. This existing evidence suggests that Saffron has the potential to be used efficaciously to alleviate the symptoms of depression in different conditions, from premenstrual to post-partum. On the contrary, this statement has to be supported by more clinical evidence and large-scale trials among these areas of study to address methodological limitations and a lack of global diversity in clinical recommendations. A broader perspective can open avenues for a detailed mechanistic approach, proper dosage, more bioactive composition, and long-term safety in the herbal industry. However, natural compounds have significant challenges, such as low bioavailability.

Furthermore, natural compounds are generally rapidly metabolized and can cross the blood–brain barrier. Perhaps these challenges could be overcome by developing site-specific nanocarriers that target the diseased subset of neurons instead of affecting healthy neurons. The targeted delivery of natural compounds to the affected part of the brain can result in designing a system that includes reduced side effects, the controlled release of particular drugs, and a higher drug bioavailability in a specific site. Therefore, brain delivery of natural inhibitors through a nanocarrier-based approach is futuristic, will contribute to potential CNS therapies, and will allow a novel strategy for Saffron in therapeutic applications.

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Original paper reference; Siddiqui SA, Ali Redha A, Snoeck ER, Singh S, Simal-Gandara J, Ibrahim SA, Jafari SM. Anti-depressant properties of crocin molecules in saffron. Molecules. 2022 Mar 23;27(7):2076.