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]^[1][2]. Crocetin and its glycosidic analogues crocin, picrocrocin, and safranal are regarded as the most notable bioactive molecules [56]^[3]. 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]^[4]. Research has found safranal to act on neurological disorders. For instance, safranal proved to be an effective anti-convulsant in mice, whereas crocin did not [58]^[5]. Similarly, Hosseinzadeh and Sadeghnia [59]^[6] found safranal to be protective against seizures in rats. Other studies on mice have attributed anti-depressant properties to safranal and crocin via the mechanism of inhibiting dopamine, serotonin, and norepinephrine reuptake [60,61]^[7][8].

Crocetin (Figure 1B) and crocins were shown to inhibit in vivo and in vitro angiogenesis, with crocetin being more effective [66]^[13]. Thus, crocetin could possibly be employed to retard abnormal blood vessel growth. Furthermore, crocetin has been shown to be anti-carcinogenic. Its mechanisms include the inhibiting synthesis of nucleic acid, enhancement of anti-oxidative systems, apoptosis initiation, and growth hindrance of signaling pathway factors [67]^[14]. Conflictingly, Escribano et al. [68]^[15] attributed no cytotoxic effect to crocetin, whereas the other three compounds did inhibit cell growth.

Crocins, the molecules of subject in this preseaperrch, 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]^[16]. Moreover, it has in vivo been shown to relieve cerulein-induced pancreatic inflammation [70]^[17]. Furthermore, crocins can alleviate neurological disorders. Georgiadou et al. [71]^[18] alleviated manually induced schizophrenia-like behavior in rats by administering crocins. Lastly, crocins exhibited anti-depressant activity through neurotransmitter reuptake inhibition. This has been demonstrated in vivo and in vitro [61,72,73]^[8][19][20]. Notably, crocetins are more readily absorbed than crocins in the gastrointestinal tract of animals [74]^[21]. Additionally, crocins are metabolized to crocetins when administered orally [74,75,76]^[21][22][23]. However, it has not yet been elucidated how readily crocin is metabolized in humans. Nevertheless, the method of administration must be significant for pharmacokinetics.

Picrocrocin (Figure 1C), a colorless, bitter-tasting compound, shares therapeutic effects with the other three compounds (e.g., anti-carcinogenic) [68]^[15]. However, to the best of outhe researchers' knowledge, isolated picrocrocin studies are limited and its role as a neuroprotective agent has not been described yet [77]^[24].

Crocins are natural carotenoids, commercially obtained from the dried stigma of saffron, occurring with different esterified saccharides on a crocetin backbone, such as trans-crocetin (β-d-glucosyl)-(β-d-gentiobiosyl) ester (named trans-3-Gg), trans-crocetin di-(β-d-glucosyl) ester (named trans-2-gg), trans-crocetin di-(β-d-gentiobiosyl) ester (named trans-4-GG; Figure 1D), trans-crocetin (β-d-gentiobiosyl) ester (named trans-2-G), cis-crocetin (β-d-glucosyl)-(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]^[25]. Moreover, the main interest in this herb could be due to its anti-anxiety, anti-convulsant, and hypnotic properties. It is believed that bioactive compounds such as crocin, crocetin, and others are attributed for their anti-oxidant properties, which may partly justify their neuroprotective effects [79]^[26].

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]^[27]. It was concluded from the human and animal studies that saffron, mainly crocin, has shown a positive effect in the treatment of mild to moderate depression, which might be possibly due to the interaction of serotonin and the noradrenaline system [81]^[28].

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 the saffron was more effective in guinea pig ileum [82]^[29]. 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. Saffron (60 mg/kg body weight, i.p.) significantly increased learning and memory in normal and old mice after a week of administration, demonstrating cognitive-enhancing properties [83]^[30]. 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]^[31].

Some clinical studies have shown that in a randomized and double-blind study, saffron supplementation statistically improved the mood of subjects compared to the placebo group. For 6 weeks, the administration of saffron extract (30 mg/day) was effective 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 anti-depressant known as an SSRI [85,86]^[32][33]. The therapeutic benefits of petals of saffron in the treatment of mild to moderate depression have also been suggested [87]^[34]. The efficacy of the co-administration of a hydro-alcoholic extract of saffron (40 or 80 mg) and fluoxetine (30 mg/day) was also investigated in a double-blind, randomized clinical trial for 6 weeks. The results revealed that a dose of saffron of 80 mg plus fluoxetine was more effective to treat mild to moderate depressive disorders than that of saffron of 40 mg and fluoxetine [88]^[35].

3. Pharmacological Treatment of Depression with Crocin

Several pharmacological activities have been suggested to be involved in the anti-depressant-like effects (Table 31). In the following section, we discuss these potential treatments and effects 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 anti-depressants; 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 anti-depressants such as imipramine and fluoxetine in mild to moderate depression [85,86]^[32][33]. Similarly, saffron was equally effective as citalopram in the major depressive disorder with anxious distress [107]^[36] and decreased mild to moderate generalized anxiety disorder when compared with sertraline [108]^[37]. ^42]. Additionally, there was significant decrease in the treatment of depression during premenstrual syndrome [114]^[43]. Crocin showed lower symptoms of depression in subjects with metabolic syndrome [115]^[44]. Saffron comparably improved depression and dysfunction such as reduced homocysteine levels in patients with major depression [116]^[45]. Affron^®, a standardized extract from saffron, showed a significant reduction in mild to moderate youth anxiety and depressive symptoms [117]^[46]. As mentioned in the above studies, the stigma of saffron showed a significant decrease in mild to moderate depression [118]^[47] and the petals of saffron were used to improve signs of major depression [109]^[38]. When compared to fluoxetine, saffron reduced depression and improved the lipid profile [120]^[49]. Crocin also showed a significant decrease in major depression [121]^[50]. Similarly, crocin had effects on psychological parameters in patients under methadone maintenance treatment to improve depression-like symptoms [122]^[51]. Results revealed that there is huge 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 accepted against major depression. Table 31 depicts an overview of studies employing saffron and crocin as an anti-depressant. Crocins have been demonstrated to be potentially applicable as an anti-depressant. However, crocins have been found as poorly bioavailable, with a small percentage permeating the digestive tract [124]^[53]. Furthermore, crocins are deglycosylatized into crocetin through hydrolysis when orally ingested [56,124,125]^[3][53][54]. Intra-peritoneal injection does allow unaltered crocins to penetrate the blood–brain barrier [126]^[55]. Nevertheless, drug stability and bioavailability should be increased to not hamper the desirable administration route of oral ingestion. Nanocarriers have been demonstrated to be applicable aids in biological delivery processes [119,123,127]^[48][52][56]. Various matrices have been shown to increase and retain crocins, increasing delivery and stability (Table 42). 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. Other parts of saffron such as petals proved to be effective on the HAM-D in the treatment of depression [109]^[38]. 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]^[34]. Even in a randomized, clinical trial, fluoxetine was given with the regulated amount of saffron (40 and 80 mg/day) and showed promising results in the treatment of mild to moderate depression [88]^[35]. Saffron significantly decreased the mild to moderate depression in those with post-menopausal hot flashes when compared to fluoxetine [110]^[39]. Saffron stigma was shown to reduce mild to moderate post-partum depression in mothers [111]^[40]. It was also found to be effective during mild to moderate depression in patients suffering from post-percutaneous coronary intervention [112]^[41]. 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]^[