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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 181-187

Clinical evidence on the effects of saffron (Crocus Sativus L.) in anxiety and depression


Department of Pharmaceutical Chemistry, School of Pharmaceutical Science, Lovely Professional University, Phagwara, Punjab, India

Date of Submission26-Jan-2021
Date of Acceptance12-Mar-2021
Date of Web Publication13-Jul-2021

Correspondence Address:
Pankaj Wadhwa
Department of Pharmaceutical Chemistry, School of Pharmaceutical Science, Lovely Professional University, Phagwara - 144 411, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_35_21

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  Abstract 


Crocus sativus L., a member of the Iridaceae family, commonly known as saffron has very much popular as both medicine and spice. Earlier saffron was used as one of the important constituents in opioid preparations for pain relief. Its uses in the treatment of mild-to-moderate depression are well documented. Depression can affect the quality of life of individuals by causing headaches, difficulty in thinking, and loss of interest. Many clinical trials have been conducted for evaluating the efficacy of saffron in depression cases. Almost fifty constituents of C. sativus L are well known. Few of the major constituents include crocin, picrocrocin, and safranal. In the present review, the main focus is on the antidepressant effects of saffron and its major constituents, in which it was found that saffron has substantial effects on depression and anxiety because of double-blind study the data can be trusted.

Keywords: Anxiety, Crocus sativus L, depression, double blind, saffron, safranin


How to cite this article:
Kumar V, Kaur N, Wadhwa P. Clinical evidence on the effects of saffron (Crocus Sativus L.) in anxiety and depression. World J Tradit Chin Med 2022;8:181-7

How to cite this URL:
Kumar V, Kaur N, Wadhwa P. Clinical evidence on the effects of saffron (Crocus Sativus L.) in anxiety and depression. World J Tradit Chin Med [serial online] 2022 [cited 2022 Dec 10];8:181-7. Available from: https://www.wjtcm.net/text.asp?2022/8/2/181/321340




  Introduction Top


Depression is a common mental disorder, identified by the tenacious loss of mental stability and mood swings. The mood swings and loss of interest in any activity are due to the psychological and biological changes in the brain during the depression.[1] Severe cases of depression may lead to suicidal attempts. The loss of mental stability includes abnormal sleeping, concentration in activity, behavior with others, and daily routine abnormality. Some physical changes can also be seen in patients having depression such as body weight loss, weakness, instability, loss of appetite, and poor at work.[2] It is a worldwide illness with 264 million people suffering it. People from low-income regions are not supposed to get any treatment although it is available. The global prevalence is about 17% which makes global important for this disease. Various organizations are working to help people by making them aware.[3] Depending on the frequency of the attack, depression is categorized into two: (i) recurrent and (ii) bipolar. The bipolar depressive stage is the initial stage of depression which when becomes frequent, is said to be recurrent depression. A person having bipolar may have depression in future, but in the case of depression, some symptoms might prevail but may or not have it. There are different stages of bipolar, in which the patient may experience the symptoms of mania, hypomania, depression, and bipolar which is known as the mixed stage. Whereas low esteem, reduction in sexual drives, mood swings, and feel of less affectionate are common symptoms among all. However, both stages are assassinating if left untreated.[4] Depression develops from the regular abnormal social and psychological factors and somehow environmental factors also affect mental health. The thread-like stigmas of the flower of saffron derived from the plant “Crocus sativus L.” are said to be effective in depression. Various research and experiments have shown the effectiveness of saffron in treating depression against blind, double-blind, or placebo treatment.[5] This present review covers the experimental evidence of the effect of C. sativus Linn. to tackle depression.

Saffron is a spice that is obtained from the dried stigmas of the flower of “C. sativus L.” It has thread-like stigmas that range from crimson to pale yellow in color. Saffron belongs to the plant family Iridaceae.[6] This kind of plant is mainly found in the region of Australia, China, Germany, Macedonia, Switzerland, Iran, and India. It is a native plant of Jammu and Kashmir and Himachal Pradesh in India when the climate is slightly warm in subtropical areas.[7] The flowers of saffron are collected early in the morning, and styles are differentiated from the flower just after collecting them. Thereafter, styles are dried at a mild heat for 30–40 min. They can be dried in direct sunlight also but often it is not preferred. A small number of stigmas are produced by the flowers so, to get 1 kg of saffron approximately 0.1 million flowers must be collected and harvested.[8] Saffron is used as a colouring agent, enhances the glow on the face but mainly it is being used as a spice in the Asian region. In Ayurveda, its infertility and impotence treating character are mentioned. It is being used to treat arthritis and liver enlargement.[9] Talking about the chemistry of the C. sativus L., chemical constituents are divided into volatile which consist of oils and nonvolatile compounds which consist of the various flavonoids, terpenes, and their alcoholic derivatives. It consists of more the twenty types of volatile oils which give it an extraordinary essence. Even various nonvolatile compounds such as crocin, picrocrocin, and crocetin are present. Quercetin and kaempferol are flavonoid constituents that are present in minute quantities. The unique color of saffron is due to crocin and its ester derivative constituent. Picrocrocin and safranal are among the chief constituents which are responsible for their antidepressant and anti-anxiety activity. Various essential oils and monoterpene aldehydic derivatives are responsible for the unique aroma of saffron. Since it has aromatic and coloring properties, it is being used in the cosmetic industry for the same.[10] Each different chemical constituent either chief or additive has a specific pharmacological activity that is beneficial for use as medication and is shown in [Table 1] and [Figure 1].
Figure 1: Molecular structure of crocin (1), crocetin (2), picrocrocin (3), and safranal (4)

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Table 1: Main chemical constituents/metabolites and their biological activities

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Volatile and nonvolatile chemical components present in saffron

  1. Nonvolatile chemical constituents: A chemical profile was reported after analyzing Saffron indigenous to Kashmir. The analysis was done by methanolic extract of saffron using liquid chromatography coupled to tandem mass spectrometry (MS). The researchers identified thirty chemical compounds with phenolic and flavonoid nature. These compounds are listed in [Table 2].[16]
  2. Volatile chemical constituents: As saffron has a wide range of positive health effects, many researchers are interested in knowing its volatile as well as nonvolatile components. Enormous mass spectroscopy techniques such as gas chromatography (GC)-MS, solid-phase microextraction gas chromatography -MS, and proton transfer reaction time-of-flight (PTR-TOF-MS) have been used to date for the identification of different volatile organic components of C. sativus L. PTR-TOF-MS used stigma and petals for identification purposes [Table 3] and [Table 4].[17],[18]
Table 2: Nonvolatile chemical components in saffron along with molecular mass

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Table 3: Volatile chemical components in the stigma of saffron and their molecular mass

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Table 4: Volatile chemical components in petals of saffron and their molecular mass

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Pharmacokinetics of governing chemical constituents of saffron

The main four chemical components crocin, picrocrocin, crocetin, and safranal have been identified as the most potent components to produce therapeutic effects. Usually, crocin and crocetin show good pharmacological effects, but the conversion of crocin into crocetin within the intestine occurs only when it is administered orally. Now, this crocetin is absorbed into the bloodstream. It can also be administered intravenously. As the interactions between albumin and crocetin are weak, it can easily get distribute in different parts/tissues in the body and can pass blood-brain barrier. Fecal elimination is the only route for the excretion of toxins and metabolites [Figure 2].[19]
Figure 2: Pharmacokinetic of Crocus sativus L. chemical components[19]

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  Methodology of Review Top


Various databases such as Pubmed, researchgate, and Google Scholar were used and screened for relevant literature available. The screening was based on the title and keywords mentioned above. Then, all the selected papers were screened based on the relation between depression and saffron with its pharmacological effects. All available recent literature were selected for review and added with the latest updates.


  Experimental Evidence Top


Recently, research conducted by Akhondzadeh et al. on treatment correlation between the pharmacological effects of saffron against depression and anxiety found satisfactory evidence. This investigation was about comparing the effects of ethanolic extract of the stigma of C. sativus L. and imipramine in mild-to-moderate depression. They prepare the tablets of the C. sativus L. using the powdered form of stigmas in 1.8 l of ethanol as a solvent by percolation the stigma powder. Then, the ethanolic extract was concentrated at a temperature range of 34°C–40°C. A tablet containing 10 mg dried extract was prepared for the evaluation. The efficacy of tablets was evaluated on 30 patients who were in their 4th stage of depression ranging from an age of 18–55 years, regardless of their history. All the patients underwent clinical investigation of their disease using the Hamilton Rating Scale for Depression. All the thirty patients were having a minimum score of 18 on the scale of Hamilton Rating Scale for Depression. Patients were kept in the isolated form so that the previous effects of all the psychotropic drugs were used in treatment. Then, patients were divided into two groups of equal parts. Group I was given 30 mg of the saffron (10 mg tablet thrice a day). Group II was given with an imipramine capsule of 100 mg (thrice a day). Both groups were medicated for a period of 6 weeks. All the patients were going under a casual checkup to their psychiatrist after every week. Then, after completion of the trials, all the patients were evaluated on the Hamilton Rating Scale. All the patients who had the saffron tablets were showing a significant improvement in their mental health. The mean score of Group I (saffron tablet) on the Hamilton Rating Scale was 9.20 and Group II (imipramine group) was at 9.00 on the same scale. So as a conclusion, no significant difference was seen throughout the trial, except the side effects such as anxiety, dry mouth, nausea, and headache.[20] These side effects are as usual during any research but another experiment by Akhondzadeh et al. proved it more than usual. A clinical trial was conducted to evaluate the efficacy of the ethanolic extract of the stigma of C. sativus L. against a placebo-controlled treatment through an assay. This efficacy was evaluated in patients having depression ranging from mild to moderate. A tablet of dried extract of C. sativus L. was prepared to have 15 mg of the dried extract. A total of 40 patients were considered for the trial, ranging from an age of 18 to 55 years regardless of their history, but all were having a depression of a minimum of 18 on a scale of the Hamilton Rating Scale for Depression. The whole group was kept isolated, under the supervision of experts for 4 weeks before trials. This isolation was to remove all the metabolites of the psychotropic drugs from their body, previously used for their treatment. The patients were randomly selected for the saffron capsule which was named Group I and Group II was selected for placebo-controlled treatment. Group I was given a dose of 30 mg (15 mg tablet twice a day) and Group II was given a placebo of the same shape, size, and weight for a period of 6 weeks. The patients were kept blind to all these randomizations of the treatment. A total of 35 patients completed the trials, and the patients left the treatment in between were 4 from Group I and 1 from Group II. However, after evaluation of efficacy, the total difference between the mean of the depression score on a scale of Hamilton Rating Scale for Depression was only 5. Some factors could be the reason for this difference such as age, sex, lifestyle, and mental stability. Hence, saffron can be an alternative for the drugs of mild-to-moderate depression as it has no significant side effects.[21] The results were so satisfactory that the experiment took the shape of a series of clinical trials to establish saffron as a treatment option for depression and anxiety. Hence, in 2007, Akhondzadeh et al. performed a clinical trial using 8 weeks comparing the effects of the dried ethanolic extract of powdered petals of C. sativus L. and the drug fluoxetine on depression. The tablets of dried extract of petals were prepared. Each was having 15 mg of the dried extract. The concentration of active constituents was 1.65–1.75 mg crocin and 0.13–0.15 mg safranal. Then, screening of the patients was done based on a minimum score of 18 measured on the Hamilton Rating Scale for Depression. The age and the history of the patients were not much considered for screening. The patients were randomly divided into two groups. Group A was getting 10 mg of fluoxetine (BD) double blindly. Group B was getting 15 mg of the saffron tablet (BD) for a period of 8 weeks. After completion of the trials, each patient underwent an evaluation of results which was measured by the Hamilton Rating Scale for Depression. The score was considerably decreased to a mean value of >7 which was 18 as baseline score (Day 0). Hence, except for some side effects, there were no major differentiable effects seen in the treatment of both groups. Hence, this was a step forward to use saffron as an alternate for depression ranging from mild to moderate.[22] Another satisfactory result gave birth to the idea to conduct another trial which was in 2009. Hence, Akhondzadeh et al. in 2009 after getting various shreds of evidence activity of ethanolic extract of stigmas of C. sativus L. against depression tried to evaluate the effect of C. sativus L. in Alzheimer's disease against donepezil (a drug used to treat Alzheimer's disease) – double-blind trial. A total of 91 patients were screened, out of which 37 patients were excluded from the trials due to not meeting the criteria or some other reasons. Fifty-four students who underwent the trials were evaluated for the disease condition using Alzheimer's disease Assessment Scale (ADAS) cognitive subscale, and Clinical Dementia Rating Scale – Sums of Boxes. The capsule of saffron as having 15 mg of dried ethanolic extract of the powdered stigmas of saffron. Their quality indicating active constituents such as 1.65–1.75 mg crocin and 0.13–0.15 mg safranal was present when checked using absorbance in a spectrophotometer at 330 and 400 nm. Selected 54 patients were randomly and double blindly divided into two groups, in which 27 patients were getting 30 mg of the saffron tablet (15 mg twice a day; Group A). Other 27 were given with capsule donepezil 10 mg/day (5 mg twice a day; Aricept from Pfizer; Group-B) for a period of 22 weeks. The patients were kept under supervision considering the score of the initial day as the baseline of treatment. A total number of 7 (4 from Group-A; 3 from Group-B) left the treatment in between due to some reasons. In the initial days (the Greenhouse–Geisser corrected: df = 1, P = 0.89) on a scale of ADAS in both groups, but the difference between the effects of both drugs was not significant (df = 52, P = 0.97). The baseline was 3.50 and 3.77 for saffron and donepezil, respectively.[23] Now, the literature was enough to perform analysis on the available data. Hence, Hausenblas et al. surveyed the literature available on the effects of C. sativus L. on depression (mild to moderate). The available data were compared with some standard antidepressant drugs. The objective of a meta-analysis of the saffron was to understand the pattern of effect of saffron on depression and use it as a supplement that can decrease the symptoms of depression. Significantly, it was found that the saffron has no differentiable effect when compared with imipramine but has a significant effect when compared with the placebo-controlled treatment. It has no difference in activity compared with the citalopram. The data were assessed, and the weight means the effect of the saffron supplement was prepared against placebo and antidepressant drugs. This calculation was made using the Jadad score and computer software Comprehensive Meta-analysis 2. A significant effect of saffron supplements on depression symptoms was reported. The score was found to be differentiable (M ES = −0.15); previously, it was M ES = 1.62, and the P > 0.001. Hence, in their studies, saffron supplements were found to be effective.[24] Another experiment was based on a comparative clinical trial of dried ethanolic extract of C. sativus L. and citalopram on depression by Ghajar and group. A total of 66 patients (Both men and women) ranging from 18 to 55 age were selected double blindly for clinical trials. The screening of patients was done based on scores of the patient on the Hamilton Rating Scale for Depression with at least 24 and a P = 0.001. They were kept isolated and not allowed to take any psychoactive substance for 4 weeks before the trials. The tablet was prepared using a dry compression method and each tablet consisted of 15 mg of dried extract (1.65–1.75 mg crocin) as the active agent. Then, patients were double blindly and randomly divided into two groups out of which one group was getting 15 mg of saffron tablet once a day, while the other group was given 20 mg of citalopram per day in the 1st week. The dose was doubled afterward – 30 mg/day of saffron and 40 mg of citalopram till the end for 6 weeks. Six patients (3 from each group) left the trial and sixty patients completed the trial successfully. Then, at the end, all the patients underwent a casual examination which was done by their family physicians. They were found to be in good mental status. As a result of the trial, no significant effect was seen which could be differentiable between the two groups. The score on the scale was >7 and the P = 0.984. Hence, no significant difference was found between saffron and citalopram.[25] Kashani et al. carried out clinical trials on Sixty women having postmenopausal hot flashes with major depression. This was a placebo-controlled fully randomized and double-blind clinical trial. They collected the literature knowledge available and prepared a 15 mg saffron tablet from the dried ethanolic extract. They selected sixty women based on the age and menstrual status Hot Flash-Related Daily Interference Scale (HFRDIS) along with depression which was screened with Hamilton Rating Scale for Depression. Patients were also categorized according to the severity of the hot flashes. Two groups were made with random selection. One group was given a 15 mg tablet of saffron (Twice per day), while the other group was receiving the placebo of the same shape size and appearance. This treatment was carried out for 6 weeks, after which only 54 women completed the trials. The saffron tablet was able to reduce the symptoms of depression as compared to the placebo. The HFRDIS score was 10.41 with a P = 0.0001. No adverse effects were seen significantly and no difference between the frequency of their adverse events.[26] All the clinical trials and the experiments showed satisfactory results, and the evidence was enough to prove the statement.


  Other Pharmacological Activities Top


This is an ancient plant which was being used from the past many years because of its potency and pharmacological activities. Saffron has a positive effect against depression and anxiety, but apart from this, it also shows potent activities against many health issues. The brief discussion about overview of its other pharmacological activities has been discussed in the next section.

  1. Antioxidant activity: The active constituents of C. sativus L. such as safranal, crocetin, carotene, and crocin along with the phenolic content have been reported for showing antioxidant activities. Polyphenol content present in the flowers of C. sativus L. is very effective in reducing the activities of free radicals. It also helps in protecting various organs such as the lungs, heart, kidneys, and liver from oxidative effects. Crocin bleaching assay was conducted for examining the antioxidant as well as radical scavenging activity. To monitor this activity, other methods such as auto-oxidation inhibition of β-carotene in the cell lysates were performed. A good effect on pc-12 glucose/serum cell membranes was noticed which suggested that alpha tocopherols are less effective than crocin components as an antioxidant[27]
  2. Anti-inflammatory activity


    1. Anti-inflammatory activity on neutrophils: C. sativus L. has been reported to have an activity to combat inflammation of neutrophils. Safranal (0.5, 1, and 2 mg/kg) and crocin (25, 50, and 100 mg/kg) have been reported to lower the inflammation pain along with lowering neutrophil count in animal models[28]
    2. Pro-inflammatory responses on cytokinin: The administration of ethanolic aqueous extracts of saffron to a rat model with a chronic injury has been seen in decreasing neuropathic pain through decreasing the pro-inflammatory factors (tumor necrosis factor-α, interleukin [IL]-1 β, and IL-6).[29]


  3. Hypotensive activity: A study was performed where I.V. injection prepared from aqueous extract of C. sativus L. and its constituents were injected into a rat. It was seen that hypertensive, as well as normotensive blood pressure, was decreased which indicated hypotensive activity of saffron. A reduction in mean arterial blood pressure was also observed in DOCAsalt-treated anesthetized rats by using ethanolic extract and saffron petals[30]
  4. Anti-ischemic activity: An observation on rabbits where treatment with extract of C. sativus L. before the ischemic period was done. It stated that C. sativus L. can act as a membrane stabilizing agent and it can also maintain the antioxidant defense system during reperfusion. It can also reduce or maintain the Ca2+ influx as well as reactive oxygen species accumulation. In another experiment, a rabbit has treated directly with IR, thereby a reduction in left ventricular pressure, a flow in left ventricular end-diastolic pressure along with heart rate was observed. A slight recovery was seen when saffron was given before ischemia. A significant improvement was seen in cardiac performance when saffron treatment was given at reperfusion[31]
  5. Antitussive activity: Guinea pigs were treated with 20% nebulized citric acid solution, and evaluation was done using petals and stigma part of C. sativus L. safranal and crocin were injected intraperitoneally. It has been reported that ethanolic extract (100–800 mg/kg) of stigma and safranal (0.25–0.75 ml/kg) of C. sativus decreasing cough but crocin, as well as ethanolic extract of petals, did not show any antitussive effect[32]
  6. Hypolipidemic activity: Rats were artificially induced hyperlipidemia through diet and a procedure of treatment was carried out with crocin component of C. sativus L. for 10 days. A decrease in total cholesterol, very-low-density lipoprotein, low-density lipoprotein, and serum triglycerides was observed with 25–100 mg/kg of dose per day. Further, modified fat loading, as well as modified fat balance methods, indicated that crocin helps in stopping fat and cholesterol absorption. Enzyme assay as well as in situ loop methods suggested that there is an indirect relation between crocin and inhibition of fat absorption. Crocin helps in lowering fat absorption by blocking the effect of pancreatic lipase selectively[33]
  7. Anticonvulsant activity: Convulsions were induced in mice by treating them with pentylenetetrazol. A dose of 0.15–0.35 ml/kg of safranal has been reported to reduce the onset of tonic convulsions, the duration for which the seizures persist along saving the mice from death. On the other hand, there was no such effect on the reduction of convulsions when treated with crocin[34]
  8. Inhibition of genotoxicity: Pretreatment of Swiss albino mice was conducted for 5 continuous days where a dose of 20, 40, and 80 mg/kg body weight was given. This intervention suggested that the aqueous extract of C. sativus L. inhibited genotoxicity of cyclophosphamide, urethane, cisplatin, and mitomycin C [Figure 3].
Figure 3: Various pharmacological activities of Crocus sativus L

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  Conclusion Top


Depression is a frivolous disease, if not treated at times. As per the experimental evidence collected through the literature collected, it is very much clear that the ethanolic extract of the stigma part of C. sativus L. indicates effectiveness in reducing mild-to-moderate depression. The methods used were commonly randomized double blind or placebo controlled where an extract of different parts of the saffron flower was given to one group and placebo, imipramine, fluoxetine, or donepezil, etc., were given to the second group of candidates. For screening purposes, Hamilton Rating Scale was taken into consideration. Furthermore, the different chemical constituents such as safranal, crocin, crocetin, and picrocrocin have been reported as potent medications for treating various diseases. The extract of saffron along with safranal and crocin is very effective interventions as an antioxidant, antitussive, antihypertensive, anti-inflammatory, antidiabetic, and the anticonvulsant agent checked in various rabbits or mice models.

Acknowledgment

The authors are thankful to the faculty of Lovely Professional University for providing the opportunity to work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 1], [Table 2], [Table 3], [Table 4]



 

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