Studies have reported that saffron extracts and their constituents, safranal and crocins, exert antidepressant effects through an activation of serotonergic, noradrenergic and dopaminergic systems in mice submitted to the forced swim test ^[17][69]. Crocetin was found to be efficient in the treatment of depression in mice ^[18][70]. In addition, a randomized controlled trial showed that 50 mg saffron resulted in a significant decrease in the Beck depression and anxiety inventory scores in comparison to placebo treatment ^[10][62]. Moreover, combined treatment with saffron and curcumin was found to be associated with greater improvements in depressive symptoms in patients suffering from major depression disorder compared to a placebo ^[19][71].

Investigations have shown that aqueous saffron extracts and its constituent safranal exert anxiolytic effects similar to that of diazepam, probably through their interaction with the benzodiazepine binding site at the GABA_A receptor ^[20][21][22][72,73,74]. In addition, studies have demonstrated that crocins alleviated the obsessive compulsive behavior in rats through an antagonistic action at the 5-HT2C receptor site ^[23][75].

Animal studies have reported that acute supplementation with crocins improved the schizophrenia negative symptoms as reflected by the attenuation in the social isolation induced by sub-chronic treatment with ketamine ^[15][67]. Moreover, crocins were found to attenuate the psychotomimetic effects (hypermotility, stereotypies and ataxia) as well as the recognition memory deficits induced by ketamine in rats ^[15][67]. In the frame of one double-blind, placebo-controlled study, saffron aqueous extract and crocins treatments for 12 weeks were found to be safe and well tolerated in schizophrenic patients ^[16][68].

Atherosclerosis is a major histological modification of the arteries, which favors cardiovascular diseases and vascular dementia ^[35][36][87,88]. The identification of drugs allowing for the prevention of atherosclerosis is therefore of major interest. Crocetin was found to decrease the low density lipoprotein (LDL) oxidation and to reduce the vascular thiobarbituric reactive acid substances (TBARs), NF-κΒ activation, vascular cell adhesion molecule-1 (VCAM-1) expression, foam cell formation and the progression of aortic atherosclerotic lesions in rabbits treated with a high fat diet for 8 weeks ^[37][89]. The anti-atherosclerotic effect of crocetin was explained in part by the inhibition of NF-κΒ activation and VCAM-1 expression, a cytokine-inducible member of immunoglobulin gene superfamily, implicated in atherogenesis by favoring adhesion of monocytes to vascular endothelium, subsequently facilitating the extravasation into the subendothelial space ^[37][38][89,90]. Moreover, saffron was found to prevent atherosclerosis in high fat treated rats through the suppression of p38 mitogen-activated protein kinase (MAPK) pathway and inhibition of smooth muscle cell proliferation ^[39][91]. It is well known that endothelial dysfunction, which is characterized by a reduction in the bioavailability of nitric oxide (NO), is an early step in the development of atherosclerosis ^[40][92]. Tang et al. ^[41][93] have suggested that crocetin may exert its beneficial effects on atherosclerosis through an upregulation of endothelial nitric oxide synthase (eNOS) expression, thus alleviating the development of LDL oxidation-induced endothelial dysfunction. Moreover, recent studies have shown that saffron aqueous extract attenuated the progression of aortic stenosis and improved the plaque stability in apoE knockout (ApoE^−/−) atherosclerotic mice ^[42][94]. The anti-atherosclerotic effects were explained partly by the reduction in IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) expressions most likely leading to decreased formation of foam cells ^[42][94]. In the frame of a randomized placebo-controlled clinical trial, crocins treatment (30 mg/day) for 8 weeks was found to decrease the oxidized-LDL and MCP-1 levels in patients with coronary artery disease ^[43][95].

Hypertension often associated with cardiovascular diseases can be associated with atherosclerosis in certain patients. Previous studies have reported that saffron extract and its components, notably safranal and crocins, reduced the mean arterial blood pressure in desoxycorticosterone acetate (DOCA), salt induced hypertensive rats ^[44][96], in a dose-dependent manner. The same authors have shown that chronic treatment with safranal decreased the systolic blood pressure in desoxycorticosterone acetate (DOCA), salt induced hypertensive rats ^[45][97]. Moreover, investigators have suggested that saffron induces relaxation in isolated aortic rings through mainly its effect on endothelium via nitric oxide synthase pathway ^[46][98]. Recent studies have demonstrated that saffron reduces the blood pressure in an angiotensin II-induced hypertension rat model through an inhibition of the renin–angiotensin system ^[47][99]. Crocetin treatment for 3 weeks was found to decrease the systolic blood pressure in spontaneously hypertensive rats ^[30][82]. The antihypertensive effect of crocetin was suggested to be related to an increase in NO bioavailability ^[30][82]. In addition, in the frame of a double-blind, placebo-controlled study, saffron (400 mg) treatment for seven days decreased the systolic blood pressure and the mean arterial pressure in healthy humans ^[48][100]. More recently, saffron (200 mg per day) supplementation for 12 weeks was found to improve blood pressure in elderly hypertensive subjects ^[49][101]. The underlying mechanism for which saffron exerts its beneficial effect on blood pressure may be explained in part by the decrease in endothelin-1 (ET-1) levels observed in elderly patients treated with saffron ^[49][101].

Dyslipidemia associated with enhanced LDL cholesterol and/or triglyceride levels is a major risk factor in cardiovascular diseases and strongly contributes to the different steps of atherosclerosis, from its initiation (fatty streak) to its final step (atheromatous plaque). Studies have shown that saffron and crocin decrease the elevated levels of triglycerides (TG), total cholesterol (TC) and LDL cholesterol in high fat treated rats ^[50][102]. The mechanism underlying these effects was attributed to the modulation of oxidative stress as reflected by the reduction in the rise of MDA and an increase in antioxidant enzymes in high fat fed rats treated either with saffron or crocins ^[50][102]. Moreover, 10-day treatment with crocins was found to reduce serum TG, TC, LDL cholesterol and very low density lipoprotein (VLDL) cholesterol levels in high fat-induced hyperlipidemic rats. The authoresearchers sus of this study suggest that crocins exert their hypolipidemic effects partly through the mal-absorption of fat and cholesterol induced by an inhibition of pancreatic lipase ^[51][103]. In addition, one recent meta-analysis of randomized controlled trials has shown that supplementation with saffron resulted in a reduction in serum concentrations of TG and TC with an increase in HDL cholesterol ^[52][104].

Type-2 diabetes is not only a risk factor for cardiovascular diseases but also for dementia. Studies undertaken on animals have shown that saffron improves the insulin levels and lipid profile in obese insulin resistant rats. The beneficial effects of saffron on insulin resistance appeared to be associated to a decrease in oxidative stress and normalization in adiponectin levels ^[53][105]. Crocetin was also found to prevent the development of insulin resistance in fructose fed rats ^[54][106]. The beneficial effects of crocetin on insulin sensitivity appeared to be associated to the normalization of the decreased protein and mRNA expression of adiponectin at the level of adipose tissue in fructose fed rats ^[54][106]. In addition, in the frame of a randomized double-blind clinical trial, saffron (15 mg per day) supplementation for 3 months was found to significantly decrease the fasting plasma glucose, hemoglobin A1c (HbA1c), total cholesterol, LDL-cholesterol and LDL/HDL ratio in type-2 diabetic patients in comparison to baseline group ^[55][107]. The discrepancy to find similar results in the effects of saffron on glucose control parameters in other clinical studies could be explained by using different saffron concentrations, treatment durations and population samples ^[56][57][58][108,109,110].

Among the ocular degenerative diseases, AMD is currently considered as the leading cause of irreversible vision loss in developed countries ^[65][117]. Studies have shown that saffron is effective in reducing retinal degeneration in bright continuous light exposure rat models, an AMD experimental model ^[66][118]. This neuroprotective effect of saffron was thought to be attributed to its antioxidant properties and its involvement in the regulation of genes, which control the release of pro-inflammatory cytokines by glial cells ^[67][119]. Saffron treatment (20 mg/day) was found to improve focal electroretinogram (fERG) findings in one placebo-controlled study of patients with AMD ^[68][120]. Furthermore, 14 months follow-up of these patients demonstrated ongoing saffron treatment ameliorated visual acuity and fERG parameters ^[69][121]. However, in the frame of a randomized, double-blind, placebo-controlled crossover trial, saffron supplementation modestly improved the visual function in patients suffering from AMD ^[62][114]. The failure to significantly delay the progression of such chronic disease probably requires a longer period of treatment with saffron.

In streptozotocin treated rats, a model of diabetic retinopathy, saffron extract was found to protect the antioxidant reserve and to decrease lipid peroxidation in retina tissue ^[70][122]. Moreover, studies have shown that crocins decrease microglial activation in high glucose-free fatty acid BV-2 and N9 cultured cells through its antioxidative and anti-inflammatory properties ^[71][123]. The authors suggest that crocins could be used as a promising medicine agent in controlling microglial activation in diabetic retinopathy ^[71][123].

Studies have shown that oral saffron extract administration was able to reduce the rise in intraocular pressure and to prevent the retinal ganglion cell death in a model of experimental glaucoma ^[72][124]. It has been postulated that this neuroprotective effect of the saffron extract could be due to its anti-inflammatory effects and its antioxidant properties ^[72][124]. In the frame of a randomized interventional pilot study, oral aqueous saffron extract was found to exert an ocular hypotensive effect in patients suffering from primary open-angle glaucoma ^[64][116]. Further studies should be undertaken to determine the mechanisms for which topical saffron components could ameliorate the glaucoma disease.

Retinitis pigmentosa is a genetic degenerative disease. Investigations have demonstrated that dietary supplementation with safranal slows photoreceptor cell degeneration and improves the loss of retinal function and vascular network disruption in the P23H rat models of autosomal dominant retinitis pigmentosa ^[73][125]. The underlying mechanisms for which saffron exerts its beneficial effects appears to be mediated through the prevention of the increase in peroxide-induced oxidative damage and inhibition of caspase-mediated apoptosis ^[74][75][126,127].

Saffron and crocins were found to inhibit beta-amyloid aggregation, a key step in the pathogenesis of Alzheimer’s disease ^[76][77][128,129]. In an Alzheimer’s disease rat model induced by streptozocin intra-cerebroventricularly, studies have shown that crocins (30 mg/kg) are effective in antagonizing the learning and memory impairments. Moreover, recent investigations have shown crocins to improve cognition and memory abilities and reduce Aβ_1-42 content in cerebral cortex and hippocampus in a mouse model of Alzheimer’s disease induced by D-galactose and aluminum trichloride ^[78][130]. The same study showed crocins to increase the levels of glutathione peroxidase, superoxide dismutase and choline acetyltransferase, and decrease the levels of ROS and acetylcholinesterase in the cerebral cortex and the hypothalamus. The authors concluded that crocins seem to exert beneficial effects on the development of Alzheimer’s disease partly through its antioxidant and anti-apoptotic properties ^[78][130]. In the frame of a double-blind-placebo-controlled study, 30 mg per day supplementation with saffron for 16 weeks resulted in improved cognitive function in patients suffering from mild to moderate Alzheimer’s disease ^[79][131]. Moreover, the follow-up of this researchtudy in which the authors evaluated the effects of saffron (30 mg/day) for 22 weeks showed that saffron was as effective as donepezil in the treatment of mild-to-moderate Alzheimer’s disease ^[80][132]. It is noteworthy that saffron extract and donepezil treated patients presented similar adverse events (AEs) frequency with the exception of vomiting, which occurred more frequently in the donepezil group ^[77][129]. In addition, a recent systematic review of clinical trials demonstrated that saffron was equally effective as commonly used drugs for Alzheimer’s disease and resulted in no difference in the incidence of side effects ^[81][133].

The characterized neuropathology of Parkinson’s disease patients is the selective progressive degeneration of dopaminergic neurons in the substantia nigra (SN) leading to a depletion of projecting dopaminergic nerve fibers in the striatum ^[82][134]. Moreover, accumulation of endogenous 6-hydroxydopamine (6-OHDA), which is a neurotoxin that selectively destroys dopaminergic and noradrenergic neurons in the brain, has been identified in patients with Parkinson’s disease ^[83][135]. Interestingly, studies have reported that crocetin protected the substantia nigra neurons against the deleterious effects of 6-OHDA through the preservation of reduced glutathione (GSH) and dopamine levels and the attenuation of TBARs in a 6-hydroxydopamine (6-OHDA) rat model Parkinson’s disease ^[84][136]. Moreover, in the same animal model, crocins improve memory performance. The authors suggested that the beneficial effects exerted by crocins on memory in Parkinsonian rats, are mediated, at least in part, through reducing TBARs and nitrite (NO₂⁻) levels in the hippocampus ^[85][137]. In another animal model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), crocetin treatment was found to attenuate the motor deficits and to preserve dopaminergic neurons in association with the protection against mitochondrial dysfunction by blocking the mitochondrial permeability transition pore (mPTP) opening ^[86][138].

Muscle weakness is generally defined as a temporary or permanent loss of muscle strength. Under its more severe form, it is defined as sarcopenia ^[87][139]. It is usually due to a lack of exercise, muscle injury, pregnancy or aging. It can also occur with long-term conditions, such as diabetes or heart disease. The effect of saffron in the management of muscle weakness has been described. In this context, the effect of saffron on physical performance in 28 healthy men has been studied. This enstrudy indicated that saffron supplementation (300 mg/day or 10 days) increased muscle strength and improved reaction time. Results indicated that saffron treatment improved mitochondrial function as well as blood flow and oxygen delivery to the muscles during exercise ^[88][140]. Previous studies have suggested that saffron contains two beneficial carotenoids called crocin(s) and crocetin ^[89][141], which are associated with the prevention of muscle fatigue and weakness. On this basis, Lei et al. indicated that crocins relieve pain and muscle suffering in osteoarthritis rats triggered by MNX surgery ^[90][142]. They also showed that crocins can reduce oxidative stress and inflammation induced by osteoarthritis. Oxidative stress may be involved in the pathogenesis of muscle dysfunction and inflammation. Indeed, ROS oxidize various components of the cell and can lead to cellular injury and even cell death ^[91][143]. The result of these disturbances is a cellular dysfunction leading to inflammatory disorders ^[92][144]. The elevation of ROS production and alteration of antioxidant enzyme systems leads to muscle loss and weakness ^[93][145]. Crocins treatment attenuated oxidative stress and improved the muscle strength. It has been reported that crocins can increase the activities of GSH reductase and gamma-glutamyl cysteine synthetase (gamma-GCS); hence, it can contribute to a stable GSH ^[94][90][43,142]. Moreover, it has been shown that crocins have an important relaxing effect on rat tracheal smooth muscle cells ^[95][146]. Crocetin was also found to effectively treat and prevent physical fatigue in men ^[96][147].