Saframyl is a natural product with positive effects on psychological well-being. It is generally available in pharmacies without a prescription as a mood-enhancing dietary supplement. It is considered to be the first clinically proven natural antidepressant. Its effect is based on triple action of Satiereal®, a natural substance from saffron (Crocus sativus), L-Tryptophan amino acid and vitamin B6 (Parapharmanet, Saframyl).
Saffron has traditionally been used to flavour food. It is currently the most expensive spice in the world mostly because it has to collected by hand and specifically treated. Medicinally, Saffron has been suggested to be effective in the treatment of a wide range of disorders including coronary artery diseases, hypertension, stomach disorders, dysmenorrhea and learning and memory impairments. In addition, different studies have indicated that saffron has anti-inflammatory, antiatherosclerotic, antigenotoxic and cytotoxic activities (Javadi et al., 2013). Saffron is mostly produced in Iran, where it accounts for up to 90% of the world’s supply although Spanish saffron is reported to be of higher culinary quality (Frank et al., 2018).
According to World Health Organisation (WHO), depression is the most common psychiatric illness in the general population. Approximately 25% of people will experience at least one episode of depression during their lifetime. Women suffer from depression approximately twice as often as men and unipolar depression is the most common cause of disruption of work capacity in the world among the population aged 15 to 44 (World Health Organization, 2018). It is a chronic, life-long illness characterized by the repetition of episodes of morbid mourning and sadness causing a tremendous mental thirst and pain. Depression is burdened with high mortality, not only in suicidal behaviour (up to 15% of cases), but also at high risk of cardiac death, up to five times higher than in healthy people. There is already number of different antidepressants on the market. However, many patients do not tolerate the side effects of available medication or do not adequately respond to the treatment (Hilgers, 2010, p.358-359).
The antidepressant effect of Saframyl
The antidepressant effect of saffron-containing substances has been confirmed in many experimental and clinical studies and the use of herbal products is a popular alternative for many patients (Havlik E., 2018). Saffron (Crocus sativus) has been traditionally used in Persian medicine as a means of anti-decay and aphrodisiacs. Symptoms of depression are common accompanying phenomena of many psychosexual problems and many psychopharmacas find use in the treatment of sexual disorders as a causal or symptomatic treatment. In animal experiments, the administration of saffron extract resulted in a significant increase in sexual activity (Shamsa et al., 2009). Clinical studies:
The Figure 1 below shows a clinical trial in thirty adult outpatients who met the criteria of Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) for major depression based on the structured clinical interview. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18 (Akhondzadeh et al., 2018). In this double-blind, single-center trial, patients were randomly assigned to receive a capsule of saffron 30 mg/day (TDS) (Group 1) and capsule of imipramine 100 mg/day (TDS) (Group 2) for a 6-week study. According to Akhondzadeh et al., 2018, Saffron at this dose was found to be effectively similar to imipramine in the treatment of mild to moderate depression (F = 2.91, d.f. = 1, P = 0.09). In the imipramine group anticholinergic effects such as dry mouth and also sedation were observed more often that was predictable. These effects were similar to the effects of ?uoxetine (Noorbala et al., 2005).
Fig 1: Clinical study in 30 subjects over 6 weeks Saffron vs. Imipramine
Mean ± SEM scores of two groups of patients on the Hamilton Depression Rating Scale. ns = non-significant, ** = P < 0.01 and *** = P < 0.001. The horizontal symbols (** and ***) were used to express statistical significance versus their respective baseline value and ns symbols are for between group comparisons (Taken from AkhondzadehBasti et al., BMC Complement Altern Med. 2004 Volume 4, p.12). The Figure 2 below shows the efficacy of Saffron in the treatment of mild to moderate depression in a 6-week double-blind, placebo-controlled and randomized trial (Moshiri et al., 2006). Forty adult outpatients who met criteria for major depression according to DSM IV participated in the trial. Their baseline Hamilton rating scale for depression score was at least 18. In this double-blind, placebo-controlled, single-center and randomized trial, patients were randomly assigned to receive a capsule of saffron 30 mg a day or a capsule of placebo for a 6-week study (Moshiri et al., 2006). At 6 weeks, Saffron produced a significantly better outcome on the Hamilton depression rating scale than the placebo (d.f. = 1, F = 18.89, p < 0.001). There were no significant differences in the two groups in terms of the observed side effects. The results of this study indicate the efficacy of Saffron in the treatment of mild to moderate depression (Moshiri et al., 2006). Fig. 2: Clinical study in 40 subjects over 6 weeks saffron vs. placebo (Taken from: ?ešková, 2005, p.234). Short-term administration of saffron (30 mg/day) capsules for six weeks was also shown to be as effective as ?uoxetine (40 mg/day) in improving depression symptoms in patients who were suffering from major depressive disorder (MDD) after undergoing a percutaneous coronary intervention (Shahmansouri et al., 2014).The effectiveness of C. sativus (saffron) as a treatment for depression in human studies was summarized in Figure 3: Figure 3: The effectiveness of C. sativus (saffron) as a treatment for depression in human studies Taken from: The effectiveness of Crocus sativus (saffron) and its constituents on the nervous system. A review. Avicenna J. Phytomedicine. 2015 Sep-Oct; 5(5): 376–391(Kazdiar et all, 2015). 1. Pharmacodynamics and Pharmacokinetics of Saframyl Saframyl is an oral drug, suitable for adults and children from 12 years of age. Its main components include Safranal, L-tryptophan and Vitamine B6 (pyridoxin hydrochloride). Safranal: is a main component of Satiereal®, a patented natural ingredient extracted from saffron. It is an organic compound which exhibits high antioxidant and free radical scavenging activity, along with cytotoxicity towards cancer cells in vitro. It has been shown to have antidepressant properties in animals and pilot studies in humans (Kokosova, 2011). Molecular Formula?: ?C10H14O, Molecular Weight?: ?150.221 g/mol (Taken from Anon, 2018). (2,6,6-trimethyl-1,3-cyklohexadien-1-karboxaldehyd) L-Tryptophan: is an amino acid naturally found in plant and animal proteins. It is considered an essential amino acid because human bodies cannot make it and must be taken in the diet. It is used for some mental health disorders, for emotional symptoms in people with premenstrual syndrome or to help quit smoking. Molecular Formula: C11H12N2O2, Molecular Weight: 204.23 (Taken from Anon, 2018). (S)-2-Amino-3-(3-indolyl)propionic acid, L-?-Amino-3-indolepropionic acid. Vitamin B6 (Pyridoxin Hydrochlorid): is the 4-methanol form of Vitamin B6 which is a major cofactor in amino acid metabolism. It participates in the synthesis of serotonin and facilitates its transfer to neurons. Women use pyridoxine for premenstrual syndrome (PMS), for "morning sickness" in early pregnancy, to help in depression related to pregnancy or for symptoms of menopause (Hilgers, 2010) (Kokosova,2011). Molecular Formula: C8H12ClNO3, Molecular Weight: 205.638 g/mol (Taken from Anon, 2018). Mechanism of workSafranal inhibits the reuptake of serotonin in the central nervous system, thereby increasing its concentration in the brain and acting antidepressantly (Kianbakht and Ghazavi, 2011). Serotonin (5-hydroxytryptamine) is a monoamine neurotransmitter biochemically derived from L-Tryptophan, which participates in regulating mood, sleep, and appetite. Its deficiency causes reduced transmission of nerve impulses, resulting in mood swings, general depression, sleep disorder, irritability and aggression. Serotonin taken in the diet does not penetrate into the central nervous system, however, taking dietary supplements rich in L-Tryptophan can increase its concentration in the central nervous system. After absorbing L-tryptophan from food, the body converts it to 5-HTP (5-hydroxytryptophan), and then to serotonin (Kianbakht and Ghazavi, 2011). Vitamin B6 plays the role of the cofactor in amino acid metabolism and facilitates the transmission of serotonin to the neurons. L-tryptophan and vitamin B6 potentiate the effect of Safranal (Behjat Javadi, 2018). 2. Efficacy and toxicity Saffron has been used as a food additive for several centuries which supports its safety for most people. The ef?cacy of saffron has shown positive pharmacological effects such as anticonvulsant, anti-inflammatory, antitumor, memory-improving effects and positive effects in the treatment of mild to moderate depression. Additional effects included general improvement of fertility and premenstrual syndrome (PMS) symptoms relief (Modaghegh et al., 2008).Clinical studies have verified the effect of drug Saframyl on a depressed mood comparable with fluoxetine 20 mg/day1 or imipramine 100 mg/day2. The safety profile was documented up to a dose of 400 mg of saffron (Moshiri et al., 2015). Although, the ingestion of less than 1.5 g of saffron is nontoxic to humans, doses in excess of 5g are considered toxic and could be lethal if above 20g per day. Given that the common effective doses applied in clinical trials are considerably lower (30–50 mg/day), saffron has a wide therapeutic index. Mild toxicity with saffron induces dizziness, nausea and diarrhea while more severe toxicity causes numbness, yellowish skin and eyes and spontaneous bleeding (Moshiri et al., 2015), (Havlik E., 2018).A randomized, double-blind, placebo-controlled clinical trial by Mansoori et al., 2011, evaluated the safety of saffron administration on sexual dysfunction in 20 adult patients suffering from major depressive disorder (MDD). The individuals were divided into 2 groups receiving either 15 mg capsules of saffron or placebo twice daily. Laboratory tests including liver and renal function tests, blood cell count and coagulation tests, were assessed once before the trial and then in 4 weeks. No major laboratory changes were observed in patients receiving saffron, providing evidence for the safety of this herbal medicine (Mansoori at al., 2011).The Figure 4 shows some characteristics of clinical trials of antidepressant effect with their results: Figure 4: Characteristics of clinical trials of antidepressant effect of saffron and their results. (Taken from Moshiri M. et al., (2015), Clinical Applications of Saffron, Drug Res 2015; 65: 288). Comparison of efficacy studies saffron (30 mg extract/day) and fluoxetine (20 mg/day) in 40 patients for 6 weeks demonstrated the similar efficacy of saffron and fluoxetine as shown on the Figure 5. According to International Society for Complementary Medicine Research (ISCMR), 2004, 400 mg of saffron led to a slight decrease in systolic blood pressure and slight decrease hematological parameters, but all the changes were within the range of normal values and were not clinically relevant. Short-term therapy with saffron capsules showed the same antidepressant efficacy compared with fluoxetine in patients who were suffering from depression (Moshiri et al., 2015), (Shahmansouri et al.,2014). Fig 5: A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression. (Taken from Shahmansouri et al., 2014, pp. 216-222). Saframyl and Premenstrual syndrome (PMS) Premenstrual Syndrome (PMS) is one of the most common psychosomatic problems among women affecting 20-40% of working-age female population and depressive symptoms are a very common accompanying phenomenon of PMS. Under clinical conditions, this affirms the beneficial effect of serotonin uptake inhibitors in women with severe PMS and fluoxetine (Prozac) is considered as a treatment of choice (Hilgers, 2010). The antidepressant effect of Saframyl was evaluated in the randomized, double-blind clinical study by Agha-Hosseini at all, 2008, as shown in Figure 6 and Figure 7 below. The study involved 50 women with symptoms of PMS according to diagnostic criteria of the American College of Obstetrics and Gynecology (ACOG). All participating women had regular menstrual cycles and there were no other health problems. During the first two menstrual cycles, the gynecologist evaluated the baseline intensity of PMS symptoms and depression. Subsequently, the patients were randomized to groups that received standardized saffron extract (30 mg) or placebo during the following 2 menstrual cycles. The daily summary of symptoms was monitored, which included 17 most common symptoms of PMS including anxiety and depression (Agha-Hosseini M., 2008). Fig. 6: Overall score of PMS symptoms during the study of saffron (Crocus sativus) Fig. 7: Overall Score of Hamilton Depression Symptoms During Crocus Sativus Study (Taken from: Journal for doctors. Saframyl. 2009, p.29). In this trial, saffron was found to be effective in relieving symptoms of PMS. A significant difference was observed in the efficacy of saffron in cycles 3 and 4.Another outcome was the results of Hamilton's depression scale measured 2 days before the expected onset of menstruation. Comparing the input values ??(Cycle 1 and cycle 2) and the values ??obtained during the intervention, a significant beneficial effect of the saffron extract on the PMS symptoms (Figure 4) as well as symptoms of depression (Figure 5) was observed. No differences in frequency or severity of adverse effects were observed during the study (Agha-Hosseini M., 2008). 3. Conclusion Though there are limited human studies on the subject of saffron and depression, they are of high quality. The data presented in this paper appear to support the conclusion that Saffron and its constituents possess multiple useful effects on several diseases including depression as well as gynaecological disorders such as PMS. This appears to be a valid conclusion based on the multiple clinical studies which have shown that the nutritional supplement Saframyl, at the recommended dose, has antidepressant properties comparable to reference drugs such as Prozac and Imipramine. Its antidepressant properties are related to serotonin metabolism. Its side effects, like reduced snacking and an elevated mood could be the result of increased serotonin action in the body. Critically though and in the opinion of the author, further research is needed to determine the exact functioning of this mechanism. The safety profile was documented at a dose of 400 mg. These studies were conducted in Iran, which produces 90% of the world's saffron. In the last two decades depression has become modern epidemy among the people of all ages. This has been accompanied by a significant increase in demand for antidepressants. Throughout this thesis, the author looked at Saframyl as an alternative to currently available antidepressant drugs. Examples have been shown of clinical trials which indicate the efficacy of Saframyl in the treatment of mild to moderate depression with minimal harmful effects in the long run. Although more research is needed, saffron appears to be a promising treatment alternative to some of currently available antidepressants. However, its cost and scarcity may make its use as a dietary supplement impractical.