Saffron and Mental Health Treatment Options
11th Nov, 2020

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Saffron and Mental Health 

Absorption/Bioavailability

The research attributes the potential therapeutic value of saffron to the three main components present in the stigma: crocins, picrocrocin, and safranal.

There is limited information on the pharmacokinetics of safranal, although studies to date demonstrate low oral absorption (1). Picrocrocin has low absorptivity and bioavailability (2).

Crocins have low bioavailability after oral consumption because enzymes and intestinal microbiota rapidly hydrolyse them in the intestinal epithelium to deglycosylated trans-crocetin. Trans-crocetin is absorbed quickly by passive diffusion through the intestinal mucosa layer and distributed to body tissues including the central nervous system (CNS) (3,4,5). Crocetin is also converted to glucuronide conjugates in the liver, some of which serve as bioactive molecules in the body, while some are excreted as metabolic waste in bile or urine (6) (Figure 1).

Recently, the pharmacokinetics of a standardised saffron extract was investigated in healthy humans. The maximum concentration (Cmax) of crocetin in plasma was detected in blood 60 – 90 minutes after oral consumption of a single dose (56 mg or 84 mg), showing that crocin isomers from a standardised extract are rapidly transformed into crocetin (7). The fast presence of crocetin in blood plasma after the administration of the saffron extract contributes to understanding the beneficial effects of the standardised saffron extract observed in human clinical trials of depression and anxiety (8,9,10).

Crocetin is the only active metabolite that has been shown to be capable of crossing the blood-brain barrier and reach the CNS, regardless of whether pure crocetin or saffron extract is administered (11,12).

Figure 1. Pharmacokinetics of saffron

Pharmacokinetics of saffron

 

Mechanism of Action

Saffron and its constituents demonstrate positive effects on several neurobiological mechanisms involved in the pathogenesis of mental illness (Figure 2).

The exact mechanisms of saffron and its bioactive constituents in alleviating mood disorders are not yet fully elucidated, although evidence to date suggests multiple mechanisms:

  • Serotonin reuptake inhibition in the synaptic terminals prolongs the half-life of serotonin throughout the brain and CNS, thereby alleviating symptoms of depression. Crocin and safranal show antidepressant activity by activating the serotonergic, noradrenergic, and dopaminergic systems, inhibiting the reuptake of serotonin, norepinephrine, and dopamine (13,14).
  • Individuals with depression often exhibit alterations in HPA activity (14,15). In stress models, saffron modulates HPA axis activity by reducing cortisol concentrations (15,16,17).
  • HPA axis dysfunction can reduce BDNF levels which affects neurogenesis and neuroplasticity and are associated with depression (18). Saffron and crocin exert neuroprotective effects by increasing BDNF in stress models (19,20).
  • Crocetin can cross the blood-brain barrier and enter the CNS (20,21) and exert physiological effects on neuroprotection, neuroplasticity, and CNS activity (22). 
  • Depression is associated with immune activation and low-grade chronic inflammation. Saffron, crocin and crocetin have potent anti-inflammatory effects, inhibiting inflammatory cytokines including NF-kb, cyclooxygenase-2 (COX-2), IL-1, IL-6, and TNF-a (23,24).
  • Major depression has been associated with nitrosative and oxidative stress and specifically lowered endogenous antioxidant enzymes (25). Saffron, safranal, crocin and crocetin are potent antioxidants. They can increase superoxide dismutase (SOD) levels and glutathione availability, and decrease markers of lipid peroxidation (26,27). 
  • Saffron and trans-crocetin have antagonistic effects on NMDA and sigma-1 receptors (28,29). Overactivation of these receptors can cause neuronal dysfunction and cell death (excitotoxicity) (30,31).
  • Saffron, safranal and crocin may exert anxiolytic and hypnotic activity by interacting with the binding site of benzodiazepine in a GABA-A receptor (32).

 

Figure 2. Possible antidepressant mechanisms of action of saffron and its constituents

Saffron mechanisms of action

 

Cautions/Contraindications

Therapeutic doses of saffron and its constituents, such as those used in clinical investigations (typically 30 mg/day of extract or 120 mg of equivalent dried stigma per day), are considered safe. 

Saffron is generally well tolerated, with few adverse events reported in clinical trials. Headache, nausea, anxiety, constipation, dry mouth, and appetite changes are the most common adverse events (27,33).

Saffron has been safely used as an adjunct to antidepressant medication in clinical trials, including fluoxetine (8,34), sertraline (35) and citalopram (35). Concurrent intake of saffron and SSRI for one month is safe and has no significant effect on blood clotting, platelet count, liver or kidney function or other haematological parameters (36). 

Generally, daily doses of up to 1.5 g of saffron are considered safe in humans (37). Higher doses may cause gastrointestinal bleeding (acute dose of 2 g), toxicity (5 g), abortion (10 g) and fatality (20 g) (37). There is a caution for use in lactation, as supplementation during lactation decreased milk supply in two participants in a clinical trial (38).

 

Takeaway on saffron and mental health 

  • Accumulating evidence supports the use of saffron in treating adults with mild- to-moderate depression, and for improving depressive symptoms associated with other conditions, including menopause, PMS, post-partum depression, diabetes and metabolic syndrome.
  • The evidence suggests that saffron is effective for improving anxiety symptoms, although further studies involving clinically anxious patients is required.
  • Saffron and its constituents demonstrate positive effects on several neurobiological mechanisms involved in the pathogenesis of mental illness, including HPA axis modulating, anti-inflammatory, antioxidant, serotonergic and neuroprotective effects.
  • The potential therapeutic value of saffron is largely attributed to crocins and safranal in the stigma; however, saffron petal had equal efficacy to the stigma in reducing depressive symptoms in a clinical trial, indicating other bioactive constituents, such as phenolic compounds present in the petal, also have antidepressant effects.
  • Therapeutic doses of saffron (typically 30 mg/day) are considered safe and well-tolerated; and can be safely used as an adjunct to conventional antidepressant medication.
  • The optimal dosage, treatment duration, extract source, as well as the mechanisms of action, still need to be clarified in further high-quality, multi centred controlled.
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References
1Dogra A, Kotwal P, Gour A, Bhatt S, Singh G, Mukherjee D, Nandi U. Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure. ACS omega. 2020 Apr 23;5(17):9885-91.
2Kyriakoudi A, O’Callaghan YC, Galvin K, Tsimidou MZ, O’Brien NM. Cellular transport and bioactivity of a major saffron apocarotenoid, picrocrocin (4-(β-D-glucopyranosyloxy)-2, 6, 6-trimethyl-1-cyclohexene-1-carboxaldehyde). Journal of agricultural and food chemistry. 2015 Oct 7;63(39):8662-8.
3Dogra A, Kotwal P, Gour A, Bhatt S, Singh G, Mukherjee D, Nandi U. Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure. ACS omega. 2020 Apr 23;5(17):9885-91.
4Asai A, Nakano T, Takahashi M, Nagao A. Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice. Journal of agricultural and food chemistry. 2005 Sep 7;53(18):7302-6.
5Xi L, Qian Z, Du P, Fu J. Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats. Phytomedicine. 2007 Sep 3;14(9):633-6.
6Hosseini A, Razavi BM, Hosseinzadeh H. Pharmacokinetic Properties of Saffron and its Active Components. Eur J Drug Metab Pharmacokinet. 2018;43(4):383–90.
7Almodóvar P, Briskey D, Rao A, Prodanov M, Inarejos-García AM. Bioaccessibility and Pharmacokinetics of a Commercial Saffron (Crocus sativus L.) Extract. Evidence-based Complement Altern Med. 2020;2020.
8Lopresti AL, Smith SJ, Hood SD, Drummond PD. Efficacy of a standardised saffron extract (affron®) as an add-on to antidepressant medication for the treatment of persistent depressive symptoms in adults: A randomised, double-blind, placebo-controlled study. J Psychopharmacol. 2019;33(11):1415–27.
9Lopresti AL, Drummond PD, Inarejos-García AM, Prodanov M. affron®, a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms: A randomised, double-blind, placebo-controlled study. J Affect Disord. 2018;232:349–57.
10Kell G, Rao A, Beccaria G, Clayton P, Inarejos-García AM, Prodanov M. affron® a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. Complement Ther Med.2017;33(February):58–64.
11Linardaki ZI, Orkoula MG, Kokkosis AG, Lamari FN, Margarity M. Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminum-exposed adult mice through behavioral and neurobiochemical assessment. Food and chemical toxicology. 2013 Feb 1;52:163-70.
12Yoshino F, Yoshida A, Umigai N, Kubo K, Masaichi CI. Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain. Journal of clinical biochemistry and nutrition. 2011;49(3):182-7.
13Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC pharmacology. 2002 Dec;2(1):7.
14Shafiee M, Arekhi S, Omranzadeh A, Sahebkar A. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. Journal of Affective Disorders. 2018 Feb 1;227:330-7.
15Halataei BA, Khosravi M, Arbabian S, Sahraei H, Golmanesh L, Zardooz H, Jalili C, Ghoshooni H. Saffron (Crocus sativus) aqueous extract and its constituent crocin reduces stress‐induced anorexia in mice. Phytotherapy Research. 2011 Dec;25(12):1833-8.
16Hooshmandi Z, Rohani AH, Eidi A, Fatahi Z, Golmanesh L, Sahraei H. Reduction of metabolic and behavioral signs of acute stress in male Wistar rats by saffron water extract and its constituent safranal. Pharmaceutical biology. 2011 Sep 1;49(9):947-54.
17Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, Haghighi S, Sameni HR, Pahlvan S. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. European journal of pharmacology. 2011 Sep 30;667(1-3):222-9.
18Duman RS. Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: stress and depression. Dialogues in clinical neuroscience. 2009 Sep;11(3):239.
19Hassani FV, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. DARU Journal of Pharmaceutical Sciences. 2014 Dec 1;22(1):16.
20Dorri SA, Hosseinzadeh H, Abnous K, Hasani FV, Robati RY, Razavi BM. Involvement of brain-derived neurotrophic factor (BDNF) on malathion induced depressive-like behavior in subacute exposure and protective effects of crocin. Iranian journal of basic medical sciences. 2015 Oct;18(10):958.
21Lautenschläger M, Sendker J, Hüwel S, Galla HJ, Brandt S, Düfer M, Riehemann K, Hensel A. Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier. Phytomedicine. 2015 Jan 15;22(1):36-44.
22Umigai N, Takeda R, Mori A. Effect of crocetin on quality of sleep: a randomized, double-blind, placebo-controlled, crossover study. Complement Ther Med. 2018;41:47–51.
23Hemshekhar M, Santhosh MS, Sunitha K, Thushara RM, Kemparaju K, Rangappa KS, Girish KS. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status. Biochimie. 2012 Dec 1;94(12):2723-33.
24Xu GL, Li G, Ma HP, Zhong H, Liu F, Ao GZ. Preventive effect of crocin in inflamed animals and in LPS-challenged RAW 264.7 cells. Journal of agricultural and food chemistry. 2009 Sep 23;57(18):8325-30.
25Maes M, Galecki P, Chang YS, Berk M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro) degenerative processes in that illness. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2011 Apr 29;35(3):676-92.
26Palta P, Samuel LJ, Miller III ER, Szanton SL. Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosomatic medicine. 2014 Jan;76(1):12.
27Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human Psychopharmacology: Clinical and Experimental. 2014 Nov;29(6):517-27.
28Lechtenberg M, Schepmann D, Niehues M, Hellenbrand N, Wunsch B, Hensel A. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma~ 1 (sigma-1) receptors. Planta medica. 2008 Jun 1;74(7):764.
29Berger F, Hensel A, Nieber K. Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices. Neuroscience. 2011 Apr 28;180:238-47.
30Dantzer R, Walker AK. Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?. Journal of neural transmission. 2014 Aug 1;121(8):925-32.
31Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews immunology. 2016 Jan;16(1):22.
32Mohajeri SA, Sepahi S, Ghorani Azam A. Antidepressant and antianxiety properties of saffron. Saffron. INC; 2020. 431–444 p.
33Marx W, Lane M, Rocks T, Ruusunen A, Loughman A, Lopresti A, et al. Effect of saffron supplementation on symptoms of depression and anxiety: A systematic review and meta-analysis. Nutr Rev. 2019;77(8):557–71.
34Jelodar G, Javid Z, Sahraian A, Jelodar S. Saffron improved depression and reduced homocysteine level in patients with major depression: A Randomized, double-blind study. Avicenna J phytomedicine. 2018;8(1):43–50.
35Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: A randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2014;174:51–6.
36Mansoori P, Akhondzadeh S, Raisi F, Ghaeli P, Jamshidi AH, Nasehi AA, Sohrabi H, Saroukhani S. A randomized, double-blind, placebo-controlled study of safety of the adjunctive saffron on sexual dysfunction induced by a selective serotonin reuptake inhibitor.
37Schmidt, M., Schmidt M, Betti G, Hensel A. Saffron in phytotherapy: pharmacology and clinical uses. Wiener Medizinische Wochenschrift. 2007 Jul 1;157(13-14):315.
38Tabeshpour J, Sobhani F, Sadjadi SA, Hosseinzadeh H, Mohajeri SA, Rajabi O, et al. A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression. Phytomedicine. 2017;36:145–52.