A composition comprising safranal and rosavin for use in decreasing anxiety

Abstract

The present invention concerns a method for decreasing anxiety comprising the step of simultaneously, separately, or sequentially administrating to a subject in need thereof an effective amount of i) at least safranal, ii) at least rosavin, and iii) optionally at least one MCTs enriched oil and / or a pharmaceutically acceptable carrier.

Description

METHOD FOR DECREASING ANXIETY

[0001] This patent application claims the priority of US provisional application US 63 / 516,947 filed on August 1, 2023, which is incorporated herein by reference.FIELD OF THE INVENTION:

[0002] The present invention is related to anxiety and, more specifically to methods for decreasing anxiety and patients suffering from an anxiety disorder or from depression.BACKGROUND OF THE INVENTION:

[0003] Anxiety is a feeling of unease, such as worry or fear, that can be mild or severe. Everyone has feelings of anxiety at some point in its life. For example, someone may feel worried and anxious about sitting an exam or having a medical test or job interview. For such occasions, feeling anxious can be perfectly normal. Now, this feeling may be constant and hard to control for some people until affecting their daily lives. Such conditions are observed for people suffering from anxiety disorders, and also from depression.

[0004] Anxiety disorders are the most prevalent psychiatric disorders and are associated with a high burden of disease. With a 12-month prevalence of 10.3%, specific (isolated) phobias are the most common anxiety disorders, although people with isolated phobias rarely seek treatment. Panic disorder with or without agoraphobia (CAP) is the next most common type with a prevalence of 6.0%, followed by social anxiety disorder (SAD, also called social phobia; 2.7%) and generalized anxiety disorder (GAD; 2.2%). Evidence is lacking on whether these disorders have become more common in recent decades. Women are between 1.5 and two times more likely than men to receive an anxiety disorder diagnosis.

[0005] Depression is also a devastating psychiatric disorder generally associated with anxiety, and usually further characterized by loss of interest, sleep disturbances, lack of energy, and suicidal thoughts. Epidemiological studies show that the global prevalence ofdepression and depression-related symptoms is increasing annually. As for anxiety disorders, the prevalence of depression is higher in women (20% to 25%) than in men (7% to 12%).

[0006] Not all patients need to be treated when symptoms are mild, transient, and without associated impairment in social and occupational function. However, treatment is indicated when a patient displays marked distress or suffers from complications arising from the disorder. Anxiety disorders or depression can be treated primarily on an outpatient basis. Now, there is evidence of substantial undertreatment of these disorders

[0007] Some herbal medicines have been investigated on these patients. Now, if depression scores were decreased in some clinical studies for patients suffering from depression, their anxiety scores were mostly unchanged (SARRIS et al., Eur. Neuropsychopharmacol., vol.21(12), p:841-60, 2011).

[0008] Accordingly, there is a need for decreasing anxiety in patients suffering from an anxiety disorder or from depression, and especially for mild to moderate anxiety disorder or depression.SUMMARY OF THE INVENTION:

[0009] Now, the inventors have shown that if a specific combination of safranal and rosavin lead to a significant decrease in anxiety in patients suffering from depression, and also in patients from anxiety disorders.

[0010] This significant anxiety decrease results from the simultaneous administration of a first capsule comprising a saffron extract with safranal and being gastro-resistant, and of a second capsule with an essential oil of Rhodiola rosea comprising rosavin.

[0011] In a first aspect, the present invention relates to a method for decreasing anxiety comprising the step of simultaneously, separately, or sequentially administrating to a subject in need thereof an effective amount of:

[0012] i) at least safranal,

[0013] ii) at least rosavin, and

[0014] iii) optionally at least one Medium-chain triglycerides (MCTs) enriched oil and / or a pharmaceutically acceptable carrier.

[0015] In a second aspect, the present invention relates to products containing:

[0016] i) at least safranal,

[0017] ii) at least rosavin, and

[0018] iii) optionally at least one Medium-chain triglycerides (MCTs) enriched oil and / or a pharmaceutically acceptable carrier,

[0019] as a combined preparation for simultaneous, separate, or sequential use for decreasing anxiety in a subject.

[0020] In a third aspect, the present invention relates to a pharmaceutical composition comprising:

[0021] i) at least safranal, and

[0022] ii) at least rosavin, and

[0023] iii) optionally at least one Medium-chain triglycerides (MCTs) enriched oil and / or a pharmaceutically acceptable carrier.DETAILED DESCRIPTION:

[0024] The term subject refers to a human.

[0025] Preferably, the subject is suffering from an anxiety disorder and / or from depression.

[0026] Anxiety disorders are well known and include phobias, Generalized Anxiety Disorder (GAD), Panic disorder with or without agoraphobia (CAP), and Social Anxiety Disorder (SAD).

[0027] Depressions are also well known, and preferably correspond to depressions associated to anxiety.

[0028] Still preferably, the subject is suffering from a mild to moderate anxiety disorder and / or from a mild to moderate depression.

[0029] Typically, the Hamilton Anxiety Rating Scale (HAM-A / HARS) of said subject is equal or less than 25, preferably equal or less than 20.

[0030] Safranal or 2,6,6-Trimethylcyclohexa-l,3-diene-l-carbaldehyde (CAS N°: 116-26- 7) is an organic compound having the following formula.

[0031] It has been demonstrated that safranal has a large range of activities including anticonvulsant, antioxidant, antiproliferative, and antidepressant activities.

[0032] As used herein, the expression "effective amount" of a compound is one which is sufficient to achieve a desired biological effect, in this case decreasing anxiety. It is understood that the effective dosage will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. The ranges of effective doses provided below are not intended to limit the invention and represent preferred dose ranges. However, the preferred dosage can be tailored to the individual subject, as is understood and determinable by one of skill in the art, without undue experimentation.

[0033] Advantageously, the proportion of safranal is between 1 and 10 mg, preferably between 1.5 and 5 mg and, particularly preferably, around 2.5 mg.

[0034] In a preferred embodiment, safranal is combined with crocin or Bis[[3-D- ghicopyranosyl-(l— >6)-[3-D-glucopyranosyl] 8,8'-diapocarotene-8,8'-dioate (CAS N°: 42553-65-1), which is a carotenoid pigment having the following formula.

[0035] This compound has also a large range of activities including blood brain permeation, antioxidant, neuroprotective, antiproliferative and antidepressant activities.

[0036] Advantageously, the proportion of crocin is between 2 and 20 mg, preferably between 5 and 10 mg and, particularly preferably, around 7 mg.

[0037] Now, it should be noted that crocin and safranal are both present in saffron.

[0038] Thus, safranal and eventually crocin are preferably in the form of a saffron extract, typically a saffron dried extract. Still preferably, the particle size of the saffron extract used is less than 250 pm for at least 90% of the extract. Indeed, with such a particle size, it is possible to have a composition which benefits from very good solubility after ingestion.

[0039] Saffron comes from the cultivation of a flower of the Crocus sativus species belonging to the Iridaceae family. This flower has the particularity of having three stigmas (distal ends of the carpels of the plant).

[0040] Crocus sativus is originated from the Middle East but was first cultivated in the Greek provinces more than 35 centuries ago. This plant grows preferentially on claylimestone soils which are well watered and drained, and which also have a high organic matter content. Traditionally, raised beds are used for its cultivation, promoting good drainage, and facilitating its harvest. Budding takes place at the beginning of autumn, but it is only in the middle of this that the plant begins to flower. As soon as flowering begins, the harvest of the flowers must then be very quick and done by hand, which justifies the high cost of this spice. Indeed, in addition to the saffron flowering in a narrow window of one to two weeks after flowering at dawn, the flowers fade quickly during the day. In addition to the difficulty of harvesting, the stigmas must be quickly dried to prevent their decomposition. To do this, the stigmas are first separated on fine mesh screens which are then placed above charcoal or burning wood in an open-hearth oven where the temperature reaches 30 and 35 °C for 10 to 12 hours. Finally, the dry spice is preferably placed in an airtight glass container.

[0041] As far as the spice itself is concerned, it takes about 150 flowers to 1 g of saffron. Thus, nearly one kg of flowers is necessary to produce 12 g of saffron.

[0042] Typically, the saffron extract is between 20 and 250 mg, preferably between 50 and 100 mg and, in a particularly preferred manner, around 75 mg.

[0043] It should be noted that the saffron extract is advantageously an extract very rich in safranal with a content greater than 2% in safranal (w / w), preferably equal or greater than 4% in safranal, and a content greater than 5% in crocin (w / w), preferably equal or greater than 10% in crocin. Indeed, with such contents, it is possible to have a composition whose weight remains contained and which is easy to absorb for the subject.

[0044] According to a preferred embodiment, safranal and eventually crocin are encapsulated in a first capsule.

[0045] Suitable materials fur such a first capsule includes hydroxy propyl methyl cellulose (HPMC), pectin, polyethylene oxide, poly vinyl alcohol, alginate, polycaprolactone, gelatin, and gelatinized starch-based materials etc. Such materials are commercially available, e.g.,in the form of ribbon-like films or can be readily manufactured, e.g., by extrusion from solution.

[0046] Still preferably, the first capsule is a gastro-resistant capsule.

[0047] As used herein, a gastro-resistant capsule refers to a capsule whose disintegration occurs after the stomach, preferably in the small intestine.

[0048] Such gastro-resistant capsule can be obtained by coating the capsule material, e.g., with gum arabic, gellan gum, pectin, alginate (e.g., sodium alginate) to modify solubility properties, the extent of the effect varying according to coating thickness. Further, both pectin and alginate can be cross-linked, e.g., with calcium, this has the effect of making the material pH sensitive such that it will not dissolve in the mouth but will dissolve in the stomach where pH is lower. Multi-layer materials may also be used. Examples of suitable capsule materials and coatings are given in WO 97 / 35537 and WO 00 / 27367.

[0049] Rosavin (also known as rosin or rosarin) or 2(2£')-3-Phenylprop-2-en-l-yl a-L- arabinopyranosyl-( l ^6)-a-l)-glucopyranoside (CAS N°: 84954-92-7) is an organic compound having the following formula.

[0050] Rosavin has been reported to display immunomodulatory effects, radiation protection, anti-cancer activities, protective effects on bleomycin-induced pulmonary fibrosis, and induced antidepressant-like effects in mouse model.

[0051] Advantageously, rosavin is in a proportion of between 5 and 50 mg, preferably between 10 and 20 mg and, particularly preferably, around 15 mg.

[0052] In a preferred embodiment, rosavin is combined with salidroside or 2-(4- Hydroxyphenyl)ethyl 0-D-glucopyranoside (CAS N°: 10338-51-9), which is a carotenoid pigment having the following formula.

[0053] Salidroside was shown to improve glucose homeostasis and alleviate diabetic retinopathy and to be associated to antioxidant, anti-inflammatory, antidepressant, and neuroprotective activities.

[0054] Advantageously, salidroside is in a proportion of between 2 and 20 mg, preferably between 5 and 10 mg and, particularly preferably, around 6 mg.

[0055] Now, it should be noted that rosavin and salidroside are both present in Rhodiola rosea.

[0056] Thus, rosavin and eventually salidroside are preferably in the form of a Rhodiola rosea extract, typically a rhizome and / or root Rhodiola rosea extract. Still preferably, the Rhodiola rosea extract is a Rhodiola rosea essential oil. Now, and when combined with an MCTs enriched oil, the Rhodiola rosea extract is preferably a Rhodiola rosea dried extract.

[0057] Such Rhodiola rosea essential oil are well known from the skilled person and can be obtained by well-known method. As an example, such essential oil may be obtained by subjecting ground rhizomes of Rhodiola rosea to microdistillation / extraction in LIKENS- NICKERSON apparatus, using diethyl ether or ethanol as a solvent. The solvent may be then removed.

[0058] Rhodiola rosea (commonly golden root, rose root, roseroot, Aaron's rod, Arctic root, king's crown, lignum rhodium, orpin rose) is a plant from the Crassulaceae family growing naturally in wild Arctic regions of Europe, Asia, and North America. Even if this plant has been used in traditional medicine, there is no high-quality clinical evidence of itseffectiveness to treat any disease. The United States Food and Drug Administration (FDA) has issued several warnings to manufacturers of R. rosea dietary supplements for making false health claims about its safety and efficacy.

[0059] Typically, the Rhodiola rosea extract is between 100 and 1,000 mg, preferably between 200 and 500 mg of Rhodiola rosea extract and, in a particularly preferred manner, around 300 mg.

[0060] It should be noticed that the Rhodiola rosea extract is advantageously a rosavin rich extract, whose rosavin content is greater than 2% (w / w), preferably equal or greater than 5%. Still preferably, the salidroside content of this Rhodiola rosea extract is greater than 1% (w / w), preferably equal or greater than 2%.

[0061] According to another preferred embodiment, rosavin and eventually salidroside are encapsulated in a capsule, said capsule being the first capsule or a second capsule.

[0062] Suitable materials fur such a second capsule include hydroxy propyl methyl cellulose (HPMC), pectin, polyethylene oxide, poly vinyl alcohol, alginate, polycaprolactone, gelatin and gelatinized starch-based materials, etc. Such materials are commercially available, e.g., in the form of ribbon-like films or can be readily manufactured, e.g., by extrusion from solution.

[0063] This second capsule may be a gastro-resistant capsule or not, preferably not.

[0064] Medium-chain triglycerides (MCTs) are triglycerides with two or three fatty acids having an aliphatic tail of 6-12 carbon atoms, including caproic acid, caprylic acid, capric acid and lauric acid. As used herein a MCT enriched oil referred to an oil, whose MCTs content is greater than 40% (w / w), preferably equal or greater than 50%.

[0065] As an example of MCTs enriched oil, one can cites palm kernel oil (55% MCTs) or coconut oil (63% MCTs). Now, such MCTs enriched oil can be obtained from other sources by oils combination, fractionation and / or inter esterification. AS an example of suchcommercially available oil, one can also cites PROMIND B® commercialized by ALIANZATEAM EUROPE.

[0066] Typically, the MCTs enriched oil is between 100 and 1,000 mg, preferably between 200 and 500 mg and, in a particularly preferred manner, around 300 mg.

[0067] According to still another preferred embodiment, MCTs enriched oil is encapsulated in a capsule, said capsule being the first capsule or a third capsule .

[0068] Suitable materials fur such a third capsule include hydroxy propyl methyl cellulose (HPMC), pectin, polyethylene oxide, poly vinyl alcohol, alginate, polycaprolactone, gelatin and gelatinized starch-based materials, etc. Such materials are commercially available, e.g., in the form of ribbon-like films or can be readily manufactured, e.g., by extrusion from solution.

[0069] This third capsule is preferably not gastro-resistant.

[0070] According to a specific embodiment, i) the safranal eventually combined with the crocin are encapsulated in a first capsule, ii) the rosavin eventually combined with the salidroside are encapsulated in a second capsule, and iii) said first capsule and said second capsules are both further encapsulated optionally with the MCTs enriched oil, in a single third capsule.

[0071] Said first, second and third capsules are as described previously.

[0072] According to still another specific embodiment, the safranal eventually combined with crocin are encapsulated in a first capsule, whose first capsule is further encapsulated with the rosavin eventually combined with salidroside in a second capsule.

[0073] Said first and second capsules are as described previously.

[0074] According to still another specific embodiment, i) the safranal and the rosavin are encapsulated in a first capsule and eventually in a second capsule, whose first and second capsules are further encapsulated, optionally with the MCTs enriched oil, in a third capsule.

[0075] The first capsule and the third capsule are as described previously.

[0076] In that case, the second capsule has preferably the same characteristics than the first capsule described previously.

[0077] Advantageously, the administrating step is a daily administrating step, which is preferably done in the morning.

[0078] Still advantageously, the administrating step is done for a period of at least 4 weeks, preferably at least 6 weeks and, most preferably, for at least 8 weeks.

[0079] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0080] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0081] Other embodiments and advantages of the present invention are illustrated in the following non-limiting examples.EXAMPLES

[0082] Preparation of the SR45 formulation

[0083] 70 mg of dried saffron extract comprising at least 4% of safranal (w / w) and at least 10% of crocin (w / w) as confirmed by HPLC was encapsulated in a first gastro-resistant capsule.

[0084] 300 mg of Rhodiola rosea rhizome essential oil was further encapsulated in a second non-gastro-resistant capsule. The corresponding Rhodiola rosea rhizome essential oil comprised at least 5% of rosavin (w / w) and at least 2% of salidroside (w / w) as confirmed by HPLC.

[0085] This combination of a first and a second capsules was named SR45 formulation and administrated simultaneously.

[0086] SR45 activity on depression and anxiety

[0087] A study was conducted to measure the efficacy and safety of the use of SR45 through a randomized clinical trial to evaluate its efficiency on subjects with low mood.

[0088] The clinical trial was randomized, placebo-controlled, double-blind, with two groups depending on the product under study (placebo or SR45), in subjects with low mood who consumed 1 capsule of SR45 per day for 8 weeks.

[0089] A total of 117 subjects were included, of whom 107 completed the study. These subjects had low mood with a Hamilton Anxiety Scale score greater than 6 or a Hamilton Depression Scale score greater than 6 and complying with the following criteria:

[0090] 1. Age equal to or greater than 18 years.

[0091] 2. Subjects without psychological treatment or with psychological treatment of more than 4 weeks duration, or without psychopharmacological treatment or with psychopharmacological treatment with constant dose of antidepressants during the last 4 weeks, or with a combined treatment in which the psychological treatment has been started 4 weeks before the patient's inclusion in the study and the pharmacologist has had a constant dose of antidepressants for the past 4 weeks.

[0092] 3. Subjects who are not taking food supplements or who are taking it during the last 4 weeks.

[0093] 4. Subjects status regarding treatment (treatment yes or no) will remain the same throughout the study.

[0094] The products used in the study were:

[0095] 1. SR45, daily dose 1 capsule, orally.

[0096] 2. Placebo product, daily dose 1 capsule, orally containing Maltodextrin + Microcrystalline Cellulose.

[0097] Investigators included participants who met all protocol selection criteria. Only those participants who met all the inclusion criteria and none of the exclusion criteria were offered to participate in the study, providing them with detailed information about the procedures and tests they had to perform if they gave their consent to participate in it. In addition, the research team answered all the questions that the participant asked regarding their participation in the study.

[0098] The efficacy of the product under investigation was analyzed after comparing the differences between the groups (experimental and placebo) with respect to the evolution of the main study variable: measurement of depression and anxiety mood using the evaluation scale for depression of Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS).

[0099] The safety of investigational products (IP) was assessed by recording Adverse Events (AEs) throughout the study, from the baseline visit to the final visit. In addition, all the signs and symptoms corresponding to side effects related or not to the PI were collected after prior communication from the participant, spontaneously or by indication of the research team, and were described in the corresponding form to document tolerability to it. These forms are documented in the investigator's data collection notebook (CRD) and were recorded during study visits.[000100] The mean age of the volunteers taking SR45 was 1.79 ± 8.61 years and the mean age for the placebo group was 26.97 ± 8.87 years. There are no significant differences between these means, nor are there any between the means of body weight, height, and body mass index (BMI) of both groups under study. Therefore, it can be concluded that the groups were homogeneous before taking the treatment.[000101] The study included 51 men (25 in the SR45 group and 26 in the placebo group) and 66 women (33 per treatment group). Therefore, the population studied was also homogeneous in terms of gender.[000102] The volunteers in this study had baseline depression values of 13.56 ± 5.05 and 11.75 ± 4.30 for the group that took SR45 and for the placebo group, respectively. These values, which correspond to mild depression, do not differ significantly from each other, so it is concluded that at the beginning of the study the groups were homogeneous in terms of the depression variable.[000103 ] The volunteers began taking the assigned product (SR45 or placebo) daily and were scheduled to visit the research center twice during the 8 weeks of treatment to be measured on the Hamilton depression and anxiety scales. The visits were made on days 28 and 56.[000104] When studying the variation of the depression variable throughout the study, a decrease in its values can be seen in the SR45 group, so that the reduction in depression over time is statistically significant (p<0.05) and the individuals taking SR45 reduced their depression at the end of the study by 4.79 ± 3.68 points, representing a difference between the final and baseline visits of 8.77 points, whereas individuals in the placebo group reduced their depression less, at 6.51 ± 4.82 points, which represents a difference between the final visit and the baseline visit of 5.24 points.[000105] The fact that the placebo group also experienced a significant reduction in depression supports the correct execution of the study, since the "placebo effect" that occurs in studies carried out on mood is clearly manifested.[000106] Thus, it is observed how individuals respond to placebo, improving the symptoms of depression, just for the mere fact of knowing that they may be receiving treatment and also being subjected to monitoring and care as part of the clinical trial protocol. This instils in the volunteer expectations of improvement, enthusiasm, and a positive vision. Therefore, if the placebo group did not show changes, the correct execution of the study would have to be questioned.[000107] When comparing the treatment groups throughout the 8 weeks of the study, it was found that depression in the group treated with SR45 was reduced in a statistically significant way (p<0.05) compared to the placebo group. Therefore, individuals improve their depression due to the consumption of SR45.[000108] Regarding anxiety, at the baseline visit there were no significant differences between the two study groups (12.00 ± 5.22 and 10.96 ± 4.15 for the SR45 group and the placebo group, respectively), which means that both groups were homogeneous regarding the anxiety variable and, therefore, the final results are not influenced by differences in the starting population.[000109] The initial anxiety ranges correspond to mild-moderate anxiety levels. Both the subjects taking SR45 and those taking the placebo reduced their anxiety throughout the study in a statistically significant way (p<0.05). However, this reduction was greater in the group treated with SR45 which, starting from 12.00 ± 5.22 anxiety points, dropped it to 4.56 ± 4.04 points at the end of the study, which implies a difference of 7.44 points on the anxiety scale. The placebo-treated group showed a lesser reduction in anxiety at the final visit, 5.33 points, compared to the baseline visit. The importance of the presence of the “placebo effect” is once again emphasized, essential to ensure the correct execution of studies related to mood.[000110] When comparing the treatment groups throughout the 8 weeks of the study, it was found that anxiety in the group treated with SR45 was reduced in a statistically significant way (p<0.05) compared to the placebo group. Therefore, the individuals improved their anxiety due to the consumption of SR45.[000111 ] There were no adverse events related to the investigational products throughout the study. Therefore, it can be said that both the intake of SR45 and placebo, at the doses indicated in the study protocol and consumed for 8 weeks, were safe.[000112] Finally, the study established that: [000113] 1. Consumption of 1 SR45 capsule daily for 8 weeks reduced depression in individuals with mild depression.[000114] 2. The consumption of 1 capsule of SR45 daily for 8 weeks reduced anxiety in individuals with mild-moderate anxiety.[000115] 3. The consumption of 2 capsules of SR45 daily for 8 weeks was safe.

Claims

CLAIMS1. Products containing: i) at least safranal, and ii) at least rosavin, and iii) optionally at least one Medium-chain triglycerides (MCTs) enriched oil and / or a pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate, or sequential use for decreasing anxiety in a subject.

2. The products of claim 1, wherein the subject is suffering from an anxiety disorder and / or from depression.

3. The products of claim 1, wherein the subject is suffering from a mild to moderate anxiety disorder and / or from a mild to moderate depression.

4. The products of claim 3, wherein the Hamilton Anxiety Rating Scale (HAM-A / HARS) of said subject is equal or less than 25, preferably equal or less than 20.

5. The products of any one of claim 1 to 4, wherein: i) the proportion of safranal is between 1.5 and 5 mg, ii) the proportion of rosavin is between 5 and 50 mg, and iii) the proportion of optional MCTs enriched oil is between 100 and 1,000 mg.

6. The products of any one of claim 1 to 5, wherein: i) safranal is in the form of a saffron extract, which is between 20 and 250 mg, and ii) rosavin is in the form of a Rhodiola rosea extract, which is between 100 and 1,000 mg.

7. The products of any one of claim 1 to 6, wherein: i) safranal is encapsulated in a first capsule, which is preferably a gastro-resistant capsule, ii) rosavin is encapsulated in a second capsule, which is preferably not gastro-resistant, and iii) optionally, MCT enriched oil is encapsulated in a third capsule, which is preferably not gastro-resistant.

8. The products of any one of claim 1 to 6, wherein: i) safranal and rosavin are encapsulated in a first capsule, and eventually in a second capsule, which is preferably a gastro-resistant capsule, and ii) optionally, MCT enriched oil is encapsulated in a third capsule, which is preferably not gastro-resistant.

9. The products of any one of claim 1 to 8 for use for decreasing anxiety in a subject is done by a daily administrating step, which is preferably done in the morning.

10. The products of any one of claim 1 to 9 for use for decreasing anxiety in a subject is done by an administrating step for a period of at least 4 weeks, preferably at least 6 weeks and, most preferably, for at least 8 weeks.

11. A pharmaceutical composition comprising: i) at least safranal, and ii) at least rosavin, and iii) optionally at least one Medium-chain triglycerides (MCTs) enriched oil and / or a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherein: i) the proportion of safranal is between 1.5 and 5 mg, ii) the proportion of rosavin is between 5 and 50 mg, and iii) the proportion of optional MCTs enriched oil is between 100 and 1,000 mg.

13. The pharmaceutical composition of any one of claim 11 or 12, wherein: i) safranal is in the form of a saffron extract, which is between 20 and 250 mg, and ii) rosavin is in the form of a Rhodiola rosea extract, which is between 100 and 1,000 mg.

14. The pharmaceutical composition of any one of claims 11 to 13, wherein: i) safranal is encapsulated in a first capsule, which is preferably a gastro-resistant capsule, ii) rosavin is encapsulated in a second capsule, which is preferably not gastro-resistant, and iii) optionally, MCT enriched oil is encapsulated in a third capsule, which is preferably not gastro-resistant.

15. The pharmaceutical composition of any one of claims 11 to 13, wherein: i) safranal and rosavin are encapsulated in a first capsule, and eventually in a second capsule, which is preferably a gastro-resistant capsule, and ii) optionally, MCT enriched oil is encapsulated in a third capsule, which is preferably not gastro-resistant.

16. The pharmaceutical composition of claim 14 or 15, wherein the first capsule and the optional second capsule are both encapsulated, optionally with the MCT enriched oil, in a third capsule, which is preferably not gastro-resistant.

17. A pharmaceutical composition as defined in any of claims 11 to 16 for use for decreasing anxiety in a subject.

18. The pharmaceutical composition of claim 17, wherein the subject is suffering from an anxiety disorder and / or from depression.

19. The pharmaceutical composition of any of claim 17 or 18, wherein the subject is suffering from a mild to moderate anxiety disorder and / or from a mild to moderate depression.

20. The pharmaceutical composition of claim 19, wherein the Hamilton Anxiety Rating Scale (HAM-A / HARS) of said subject is equal or less than 25, preferably equal or less than 20.

21. The pharmaceutical composition of any of claim 17 to 20 by a daily administration, which is preferably done in the morning.

22. The pharmaceutical composition of any of claim 17 to 21 by an administrating for a period of at least 4 weeks, preferably at least 6 weeks and, most preferably, for at least8 weeks.

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