Brain disorders, i.e. neuropsychiatric and neurodegenerative diseases, have emerged as a majorproblem in recent years. Anxiety and depression are neuropsychiatric disorders that mainly result from intense interpersonal relationships, certain medications, and major stressful life events (divorce or death of a loved one, etc.). Patients suffering from mental disorders usually have symptoms like a decrease or increase in appetite, hypersomnia or insomnia, psychomotor agitation or retardation, and chronic fatigue (Breen et al., 2011). Genetic factors also contribute to the development of depression and anxiety. Chromosome 3p25-26 has been found in more than 800 families with recurrent depression (Pitsikas, 2015). In addition, one of the more common comorbidities is that of anxiety and depression (Bui and Fava, 2017). Accumulating evidence suggest that the underlying pathogenesis of anxiety and depression involve numerous common mechanisms such as control of hormones secretion, functional disturbance of GABAergic system (γ-aminobutyric acid, GABA) (Kalueff and Nutt, 2007) and dysfunction of glutamate-related nervous system (Howells and Russell, 2008; Jia et al., 2020). Furthermore, several signaling pathways involved in the regulations of oxidative stress, neuroinflammation, neurotransmitter dysfunction, and neurotrophic factors (e.g. brain derived neurotrophic factor, BDNF) also contribute to the pathogenesis of anxiety and depression (Kalueff et al., 2006; Ehsanifar et al., 2019). Therefore, treatments targeting these common mechanisms may achieve a more effective therapeutic effect. However, symptoms of depression and anxiety patients sometimes are not exactly the same. For instances, the patients with a diagnosis of major depression are more likely to show a depressed or a sad mood while the patients with a diagnosis of major anxiety mainly display an anxious or a panic mood (Clark et al., 1994). In these cases, the selection of suitable therapeutic strategy becomes more challenging and difficult (Gallagher-Michaels, 2013).

Neurodegenerative diseases are the most prevalent senile diseases in aging populations (especially those aged over 70 years), and include Parkinson’s disease (PD) and Alzheimer’s disease (AD). Cognitive decline, slow and involuntary movements, progressive dementia, and changes of personality are the common symptoms of these two diseases; however, the psychological disorder associated with PD and AD should not be overlooked. Anxiety and depression are secondary changes seen not only in neurodegenerative diseases, but also in other brain disorders. This indicates that the overlap among brain disorders is complex. Since AD and PD are multifactorial disorders without effective cures, nearly all of the drugs on the market aim mainly to alleviate the symptoms (Finley and Gao, 2017). Natural products contain multiple chemical constituents, which are more effective than single chemicals in addressing the pathogenesis of multifactorial disorders through their effects on multiple targets. This explains why drugs developed from natural products with preventive activities against brain disorders are particularly desirable. For example, sodium oligomannate (GV-971^®) is a marine algae-derived oral oligosaccharide conditionally approved in China for the treatment of mild-to-moderate AD (to improve cognitive function) in November 2019. Unlike most previous anti-PD and anti-AD drugs on the markets, by acting directly on specific target in neuronal cells, GV-971 constitutes a novel agent that therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit AD progression (Wang et al., 2019).

Saffron—the dry red stigma of Crocus sativus L—is one of the most expensive herbs on the market today. The flower of Crocus sativus L has been widely used as a natural additive in cooking to enhance flavor, color, and aroma. The origin of Crocus sativus can be traced back to the Late Bronze Age in Crete; since then, saffron has been cultivated all over the world, but especially in Mediterranean Europe, India, and south-western Asia. Cultivation of saffron requires fertile clay soil and direct sunlight under natural environmental conditions, or greenhouse conditions (which can improve yield) (Galigani and Garbati, 1999; Gresta et al., 2008; Cavusoglu et al., 2009). Saffron is referred to as “red gold,” due to the high market price attributable to hand-harvesting and low production volumes. According to an analysis of food ingredient fraud based on 677 references, saffron is one of the most commonly adulterated products (Moore et al., 2012). Thus, quality control of saffron is important for authentication. For this purpose, various chromatographic and spectrometric methods, such as UV, HPLC, GC, NIR combined with MS, and PTR-TOF-MS have been established and optimized to analyze the components of saffron (Tarantilis et al., 1995; Masi et al., 2016; Grinan-Ferre et al., 2018).

Several active ingredients are present in saffron, including carotenoids (crocin, crocetin), monoterpene aldehydes (picrocrocin, safranal), monoterpenoids (crocusatines), isophorones, and flavonoids (Rameshrad et al., 2018). The contents of these active compounds varies from region to region. Saffron has been used in traditional medicine for its hypolipidemic, anti-cancer, antioxidant, anti-inflammatory, and antidepressant properties (Rios et al., 1996). As saffron has pharmacological effects on nervous system, it has also been tested in clinical trials of depression, anxiety, AD, and other brain disorders (Moshiri et al., 2015; Hosseini et al., 2018; Samarghandian and Farkhondeh, 2020). In this review, we summarized preclinical and clinical studies of the use of saffron and its constituents for treating neuropsychiatric diseases, neurodegenerative diseases, and other brain disorders (Figure 1).

Saffron is composed of water, nitrogenous matter, sugars, soluble extract, volatile oil, and fibers, in varying amounts. Among all the components, soluble extract accounts for the highest proportion (41–44%), followed by water (14–16%), sugar (12–15%), and nitrogenous matter (11–13%) (Christodoulou et al., 2015). Saffron contains two vitamins essential to the human body: riboflavin (vitamin B2) and thiamine (vitamin B1). The riboflavin content of saffron ranges from 56 to 138 μg/g, which is the highest amount among all foods (Bhat and Broker, 1953). Apart from these two essential vitamins, small quantities of β‐carotene, essential fatty acids, linoleic and linolenic are also found in saffron. Sterols including campesterol, stigmasterol, and β‐sitosterol have been identified, as well as oleanolic, ursolic, palmitoleic, palmitic, and oleic acids. Most of the volatile compounds are terpenes, terpene alcohols, and their esters. Non-volatile compounds include picrocrocin safranal, crocetin, crocins, and flavonoids (quercetin and kaempferol), among which safranal is the major component (Pitsikas, 2015). About 150 volatile and non-volatile compounds, and nearly 50 constituents, have been identified in saffron (Boskabady and Farkhondeh, 2016). Particularly, the water-soluble carotenoid, crocin, determines saffron’s color. Picrocrocin, the glycoside of safranal, is responsible for its bitterness, while safranal provides the characteristic aroma of saffron. Saffron contains four main bioactive compounds: crocin, crocetin, picrocrocin, and safranal. These four compounds contribute to saffron’s high value and versatility in food and pharmaceuticals. We describe the chemical constituents, neuropharmacological activities, and safety profile of saffron in the following sections (Figure 2).

Crocin and crocetin exhibit very different pharmacokinetic profiles. Crocin can be hydrolyzed to crocetin before (in the gastrointestinal lumen) or during (in the intestinal mucosa) intestinal absorption (Asai et al., 2005). Although crocetin acts as the bioactive compound in rat plasma, oral administration of crocin is preferable to that of crocetin, due to the poor dissolution of the latter substance in intestinal fluid (Zhang et al., 2017). After hydrolysis, crocetin is partly metabolized into mono- and diglucuronide conjugates in the intestinal mucosa (during absorption), liver (after absorption), or both (Asai et al., 2005; Zhang et al., 2017). A clinical pharmacokinetic trial of healthy adult human volunteers showed that, after a single oral administration, crocetin reached a maximum concentration 4 to 4.8 h after administration, and was eliminated with a corresponding half-life of 6.1 to 7.5 h. The results also showed that crocetin exhibited no serious adverse reactions, even up to 22.5 mg. Due to its small molecules and hydrophilic nature, crocetin shows more rapid absorption in the portal vein than in the lymphatics when transported into the bloodstream (Umigai et al., 2011).

After intravenous injection, crocin is converted into crocetin in the gastrointestinal tract. Crocetin has a widespread distribution in tissue and low plasma concentration because of the weak crocetin-albumin interaction. Also, crocetin has therapeutic effects on neurodegenerative diseases due to its ability to penetrate blood-brain barrier (BBB) (Hosseini et al., 2017). To investigate the underlying permeation mechanisms, Lautenschlager et al. established models based on Caco-2 monolayer cells, porcine brain capillary endothelial cells (BCEC), and blood cerebrospinal fluid barrier (BCSFB). Crocin-1 could not penetrate Caco-2 monolayers even at a high concentration of 1,000 μM, which indicates its poor penetration of the intestinal barrier. In contrast, trans-crocetin not only penetrates the intestinal barrier in a dose-dependent manner, but can also gradually permeate the BBB. Instead of the paracellular rout, trans-crocetin is mostly absorbed via passive transcellular diffusion (Lautenschlager et al., 2015).

In both experimental and clinical investigations, saffron shows no significant toxicity in therapeutic doses. In acute, sub-acute, sub-chronic, and chronic toxicity tests, no marked changes have been reported in biochemical parameters, hematological parameters, or body organs, among other factors. However, as the key determinant of acute toxicity, the LD₅₀ of safranal is lower than that of saffron and crocin, which indicates greater toxicity (Bostan et al., 2017). In a sub-acute toxicity study, although safranal reduced the levels of total cholesterol, triglyceride, and alkaline phosphatase (ALP), it also increased those of lactic acid dehydrogenase (LDH) and serum urea nitrogen (BUN). Moreover, histological results indicate safranal exhibits toxicity in kidney and lung (Hosseinzadeh et al., 2013). In a short-term, double-blinded placebo-controlled clinical trial, saffron tablets were given to patients orally at a dose of 200 or 400 mg for 7 days, and showed an excellent safety (Modaghegh et al., 2008). Crocin tablets were also relatively safe in healthy volunteers at a dose of 20 mg dose for 1 month (Mohamadpour et al., 2013). In studies comparing the efficacy of saffron and placebo in patients with neuropsychiatric diseases, no serious side effects were observed (Mousavi et al., 2015; Mazidi et al., 2016; Lopresti and Drummond, 2017). As the bioactive compounds of saffron can interact with CYP enzymes, drugs with the same function will likely increase the risk of low pharmacological efficacy when co-administrated with saffron (Dovrtělová et al., 2015).

As one of the most expensive spices in the world, saffron and its constituents, such as crocin, crocetin, and safranal, have shown various biochemical and pharmacological functions. In this comprehensive review, we aimed to summarize the chemical profiles, pharmacological activities, and therapeutic applications of saffron and its constituents in diseases of the central nervous system. Both preclinical and clinical trials suggested that saffron was effective and safe without serious side effects. According to current scientific evidence, saffron and its bioactive compounds have multiple therapeutic effects in many conditions, including psychological disorders, neurodegenerative diseases, cancer, diabetes, and cardiovascular diseases. Preclinical studies proved that saffron exerts its neuroprotective effects mostly via antioxidative stress, anti-neuroinflammation, anti-apoptosis and certain other related pathways. Clinical trials also confirmed that saffron could alleviate depressive and anxiety-like symptoms in both depression and anxiety patients. Improvement of cognition impairment was observed in clinical studies using saffron for treating neurodegenerative diseases such as AD and PD. Taken together, the findings provide a fresh perspective that could aid the development of novel neuroprotective drugs from saffron and its bioactive compounds. More investigation of saffron is needed, including preclinical and clinical studies, in terms of its potential to treat neuropsychiatric diseases.

YB and CZ contributed equally to this work. All authors contributed to the article and approved the submitted version.

This study was funded by The Science and Technology Development Fund, Macau SAR (File no. 0058/2019/A1 and 0016/2019/AKP), and University of Macau (File no. MYRG2019-00105-ICMS).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.